bims-microg Biomed News
on Microglia in health and disease
Issue of 2025–05–25
89 papers selected by
Marcus Karlstetter, Universität zu Köln
  1. Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer's disease.
  2. Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration.
  3. A dynamic and multimodal framework to define microglial states.
  4. Microglia conduct the symphony of white matter degeneration in aging through T cell recruitment.
  5. Targeting C1q prevents microglia-mediated synaptic removal in neuropathic pain.
  6. A spatio-temporal brain miRNA expression atlas identifies sex-independent age-related microglial driven miR-155-5p increase.
  7. p16-expressing microglia and endothelial cells promote tauopathy and neurovascular abnormalities in PS19 mice.
  8. GADD45G operates as a pathological sensor orchestrating reactive gliosis and neurodegeneration.
  9. Mechanotransduction Activates Microglia and Impairs Phagocytosis in Stiff Amyloid-β Plaques.
  10. Immune Checkpoint PD-L1 Modulates Retinal Microglial Activation to Alleviate Vascular Leakage in Choroidal Neovascularization via ERK.
  11. SORLA Orchestrates microglial dynamics for enhanced neuroprotection and recovery following ischemic stroke.
  12. Intravenous SARS-CoV-2 Spike protein induces neuroinflammation and alpha-synuclein accumulation in brain regions relevant to Parkinson's disease.
  13. NLRX1 mediated impaired microglial phagocytosis of NETs in cerebral ischemia and reperfusion injury.
  14. Loss of insulin signaling in microglia impairs cellular uptake of Aβ and neuroinflammatory response exacerbating AD-like neuropathology.
  15. Imaging a concussion and the ensuing immune response at the blood-brain barrier.
  16. Microglial dynamics and neuroinflammation in prodromal and early Parkinson's disease.
  17. Rebamipide (Mucosta®), a clinically approved drug, alleviates neuroinflammation and dopaminergic neurodegeneration in a Parkinson's disease model.
  18. Caveolin-1 negatively regulates the calcitonin receptor-like receptor and neuroinflammation in a female mouse model of migraine.
  19. Optogenetic activation of cortical microglia promotes neuronal activity and pain hypersensitivity.
  20. Modeling hereditary diffuse leukoencephalopathy with axonal spheroids using microglia-sufficient brain organoids.
  21. MorphoCellSorter is an Andrews plot-based sorting approach to rank microglia according to their morphological features.
  22. Role of lncRNA Xist-miR-124-CCL2 axis in HIV Tat-mediated microglial activation and neuroinflammation.
  23. Betulinic acid enhances autopahgy to promote microglial M2 polarization and alleviate inflammation via AMPK-HDAC5-KLF2 signaling pathways in spinal cord injury.
  24. 11,12-Diacetyl-Carnosol Ameliorates Depression-Like Behaviors and Memory Dysfunction in CUMS Mouse Model via Inhibiting HMGB1-Mediated Neuroinflammation.
  25. Mapping Glial Autophagy Dynamics in an Amyotrophic Lateral Sclerosis Mouse Model Reveals Microglia and Astrocyte Autophagy Dysfunction.
  26. Pathways to Progressive Disability in Multiple Sclerosis: The Role of Glial Cells in Chronic CNS Inflammation.
  27. Microglia supports both the singular form of LTP expressed by the lateral perforant path and episodic memory.
  28. Single-cell sequencing and transcriptomic data reveal that P65 activation significantly promotes microglia-mediated neuroinflammation after ischemic stroke.
  29. Microglial depletion prevents visual deficits and retinal ganglion cell loss induced by early life stress in adult animals.
  30. Prostaglandin endoperoxide synthase 2 regulates neuroinflammation to mediate postoperative cognitive dysfunction in mice.
  31. M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signaling.
  32. TREM2 supports neuronal protection and microglial reactivity without an effect on misfolded protein deposition in chronic neurodegenerative prion disease.
  33. The roles of microglia and astrocytes in neuroinflammation of Alzheimer's disease.
  34. Integrative Analysis and Experimental Validation Reveal FCGR1A and ITGAL as Key Inflammatory Biomarkers in Proliferative Diabetic Retinopathy.
  35. Overexpression of TAFA4 in the dorsal root ganglion ameliorates neuropathic pain in male rats through promoting macrophage M2-Skewing.
  36. High-Fat Diet-Induced Excessive Accumulation of Cerebral Cholesterol Esters and Microglial Dysfunction Exacerbate Alzheimer's Disease Pathology in APPNL-G-F mice.
  37. Proliferating Microglia Exhibit Unique Transcriptional and Functional Alterations in Alzheimer's Disease.
  38. The regulation of microglia by aging and autophagy in multiple sclerosis.
  39. IFI204 in microglia mediates traumatic brain injury-induced mitochondrial dysfunction and pyroptosis via SENP7 interaction.
  40. Improvement of Parkinson's Disease Symptoms by Butylphthalide Through Modulation of Microglial Activation.
  41. CSF-1R ligands promote microglial proliferation but are not the sole regulators of developmental microglial proliferation.
  42. Knockdown of YTHDF2 mitigates OGD-induced microglial inflammation by preventing m6A-dependent PARP14 degradation.
  43. Inhibition of Dectin-1 alleviates inflammation in early diabetic retinopathy by regulating microglia phenotype.
  44. The Hallmarks of Ageing in Microglia.
  45. Apelin-13 enhances neurofunctional recovery and suppresses neuroinflammation via the SIRT1/NF-κB axis in ischemic stroke.
  46. The role of microglia in the development of diabetic retinopathy and its potential clinical application.
  47. Microglial activation as a hallmark of neuroinflammation in Alzheimer's disease.
  48. SIRT3 is required for the protective function of ketogenic diet on neural inflammation and neuropathic pain.
  49. Regulation of inflammation by Chaihu-Shugan-San: Targeting the IL-17/ NF-κB pathway to combat breast cancer-related depression.
  50. Soluble TREM2 ameliorates pathological phenotypes in ischemic stroke models via modulating neuronal and microglial functions.
  51. Novel fully human high-affinity anti-TREM2 antibody shows efficacy in clinically relevant Alzheimer´s mouse model.
  52. Domoic acid induces developmental stage-specific effects on microglia in zebrafish.
  53. A restarted life: Resetting microglia innate immune memory.
  54. Relaxin-2 Ameliorates Spinal Cord Injury by Inhibiting Microglia Activation.
  55. Transcranial direct current stimulation alleviates chronic pain in knee osteoarthritis by modulating microglial and astrocytic polarization and neuroinflammation.
  56. Single-Cell RNA Sequencing of the Primary Visual Cortex in Mice With Optic Nerve Injury.
  57. Microglial repopulation reverses radiation-induced cognitive dysfunction by restoring medial prefrontal cortex activity and modulating leukotriene-C4 synthesis.
  58. Icariin alleviates cognitive dysfunction by reducing neuroinflammation via the cGAS-STING pathway.
  59. Characterizing microglial heterogeneity in autophagy impairment of Paraquat-induced Parkinson's disease-like neurodegeneration.
  60. Chronic High-Fat Diet Consumption Followed by Lipopolysaccharide Challenge Induces Persistent and Long-Lasting Microglial Priming, Mediates Synaptic Elimination via Complement C1q, and Leads to Behavioral Abnormalities in Male Wistar Rats.
  61. Lectins and neurodegeneration: A glycobiologist's perspective.
  62. The Ubiquitination and Degradation of SH2B3 Mediated by MEF2A/WWP2 Axis Restores Microglial Homeostasis to Alleviate Cerebral Microvascular Endothelial Cell Injury in Ischemic Stroke.
  63. Electroacupuncture improves sleep deprivation-induced cognitive impairment by suppressing hippocampal inflammatory response in mice.
  64. Schisandrin B ameliorates Alzheimer's disease by suppressing neuronal ferroptosis and ensuing microglia M1 polarization.
  65. TREM2 deficiency exacerbates cognitive impairment by aggravating α-Synuclein-induced lysosomal dysfunction in Parkinson's disease.
  66. Chronic mild stress disrupts mitophagy and mitochondrial status in rat frontal cortex.
  67. Schaftoside restrains neuroinflammation and ameliorates cerebral ischemic injury associated with LncGm36 mediated COP1 upregulation.
  68. Anti-IL-6R antibody treatment changes microglial phenotype in AQP4 peptide-immunized mice, leading to suppression of myelitis severity.
  69. Clonidine Ameliorates Neuroinflammation in the Rat Model of Tourette Syndrome.
  70. Increased absorptive transcytosis and tight junction weakness in heart failure are equally corrected by exercise training and losartan.
  71. Cold-Induced RNA-Binding Protein (CIRP) Affects Cerebral Ischemia-Reperfusion Injury Through NF-κB Pathway.
  72. Targeting CD74 in microglia to modulate experimental cerebral ischemia and reperfusion injury: insights from Single-Cell and bulk transcriptomics.
  73. Autophagy modulation by hADSCs and green light therapy alleviates inflammation and promotes functional recovery after spinal cord injury.
  74. Evodiamine inhibits NLRP3 inflammasome-mediated microglial pyroptosis and promotes remyelination via SLC2A4-regulated autophagy.
  75. Plasma CHI3L1 associates with brain volume loss and glial activation in multiple sclerosis.
  76. Neuron-like macrophage differentiation via the APOE-TREM2 axis contributes to chronic pain in nasopharyngeal carcinoma.
  77. An AAV capsid proposed as microglia-targeting directs genetic expression in forebrain excitatory neurons.
  78. Mesenchymal Stem-Cell-Derived Exosomes Loaded with Phosphorus Dendrimers and Quercetin Treat Parkinson's Disease by Modulating Inflammatory Immune Microenvironment.
  79. Endogenous Recovery of Hippocampal Function Following Global Cerebral Ischemia in Juvenile Female Mice Is Influenced by Neuroinflammation and Circulating Sex Hormones.
  80. Salvianolic acid B exerts cerebroprotective effects after traumatic brain injury via Nrf2-dependent antioxidant and anti-inflammatory cascades.
  81. In Vitro Validation of Pulsed Electromagnetic Field (PEMF) as an Effective Countermeasure Against Inflammatory-Mediated Intervertebral Disc Degeneration.
  82. Role of biliverdin reductase, a heme degradation pathway enzyme, in the development of vasospasm after subarachnoid hemorrhage.
  83. Japanese encephalitis virus-associated human microglia induce cell death of human microvascular endothelial cells in receptor-independent infection.
  84. Aryl hydrocarbon receptor deficiency upregulates intercellular adhesion molecule 1 in retinal pigment epithelial cells and contributes to retinal inflammation.
  85. Tannic Acid-Based Injectable Hydrogel Promotes the Recovery of Traumatic Brain Injury by Anti-Ferroptosis.
  86. Mechanism of LINC01018/miR-182-5p/Rab27B in the immune escape through PD-L1-mediated CD8+ T cell suppression in glioma.
  87. Engineered Exosome-Loaded Silk Fibroin Composite Hydrogels Promote Tissue Repair in Spinal Cord Injury Via Immune Checkpoint Blockade.
  88. Protective genetic variants against Alzheimer's disease.
  89. Hypericin Regulates Inflammation Levels and Improves Depressive Symptoms in Rats With Post-Stroke Depression Through the MEK/ERK/CREB Pathway.
  1. Immunity. 2025 May 14. pii: S1074-7613(25)00192-X. [Epub ahead of print]
    Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer's disease.
    Priya Prakash, Palak Manchanda, Evi Paouri, Kanchan Bisht, Kaushik Sharma, Jitika Rajpoot, Victoria Wendt, Ahad Hossain, Prageeth R Wijewardhane, Caitlin E Randolph, Yihao Chen, Sarah Stanko, Nadia Gasmi, Anxhela Gjojdeshi, Sophie Card, Jonathan Fine, Krupal P Jethava, Matthew G Clark, Bin Dong, Seohee Ma, Alexis Crockett, Elizabeth A Thayer, Marlo Nicolas, Ryann Davis, Dhruv Hardikar, Daniela Allende, Richard A Prayson, Chi Zhang, Dimitrios Davalos, Gaurav Chopra.
      Microglial phagocytosis genes have been linked to increased risk for Alzheimer's disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a parallel decrease in free fatty acids (FFAs) and increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. Diacylglycerol O-acyltransferase 2 (DGAT2)-a key enzyme that converts FFAs to TGs-promoted microglial LD formation and was increased in mouse 5xFAD and human AD brains. Pharmacologically targeting DGAT2 improved microglial uptake of Aβ and reduced plaque load and neuronal damage in 5xFAD mice. These findings identify a lipid-mediated mechanism underlying microglial dysfunction that could become a therapeutic target for AD.
    Keywords:  Alzheimer’s disease; DGAT2; amyloid; lipid droplets; lipidomics; lipids; metabolism; microglia; neurodegeneration; phagocytosis
    DOI:  https://doi.org/10.1016/j.immuni.2025.04.029
  2. Nat Neurosci. 2025 May 22.
    Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration.
    Janos Groh, Ruoqing Feng, Xidi Yuan, Lu Liu, Dennis Klein, Gladis Hutahaean, Elisabeth Butz, Zhen Wang, Lisa Steinbrecher, Jonas Neher, Rudolf Martini, Mikael Simons.
      Aging is the major risk factor for neurodegeneration and is associated with structural and functional alterations in white matter. Myelin is particularly vulnerable to aging, resulting in white matter-associated microglia activation. Here we used pharmacological and genetic approaches to investigate microglial functions related to aging-associated changes in myelinated axons of mice. Our results reveal that maladaptive microglia activation promotes the accumulation of harmful CD8+ T cells, leading to the degeneration of myelinated axons and subsequent impairment of brain function and behavior. We characterize glial heterogeneity and aging-related changes in white matter by single-cell and spatial transcriptomics and reveal elaborate glial-immune interactions. Mechanistically, we show that the CXCL10-CXCR3 axis is crucial for the recruitment and retention of CD8+ T cells in aged white matter, where they exert pathogenic effects. Our results indicate that myelin-related microglia dysfunction promotes adaptive immune reactions in aging and identify putative targets to mitigate their detrimental impact.
    DOI:  https://doi.org/10.1038/s41593-025-01955-w
  3. Nat Neurosci. 2025 May 20.
    A dynamic and multimodal framework to define microglial states.
    Roman Sankowski, Marco Prinz.
      The widespread use of single-cell RNA sequencing has generated numerous purportedly distinct and novel subsets of microglia. Here, we challenge this fragmented paradigm by proposing that microglia exist along a continuum rather than as discrete entities. We identify a methodological over-reliance on computational clustering algorithms as the fundamental issue, with arbitrary cluster numbers being interpreted as biological reality. Evidence suggests that the observed transcriptional diversity stems from a combination of microglial plasticity and technical noise, resulting in terminology describing largely overlapping cellular states. We introduce a continuous model of microglial states, where cell positioning along the continuum is determined by biological aging and cell-specific molecular contexts. The model accommodates the dynamic nature of microglia. We advocate for a parsimonious approach toward classification and terminology that acknowledges the continuous spectrum of microglial states, toward a robust framework for understanding these essential immune cells of the CNS.
    DOI:  https://doi.org/10.1038/s41593-025-01978-3
  4. Nat Neurosci. 2025 May 22.
    Microglia conduct the symphony of white matter degeneration in aging through T cell recruitment.
    Jonathan K Monteiro, Veronique E Miron.
      
    DOI:  https://doi.org/10.1038/s41593-025-01929-y
  5. Nat Commun. 2025 May 17. 16(1): 4590
    Targeting C1q prevents microglia-mediated synaptic removal in neuropathic pain.
    Noosha Yousefpour, Shannon N Tansley, Samantha Locke, Behrang Sharif, Marc Parisien, Farin B Bourojeni, Haley Deamond, Vidhu Mathur, Nia Rahman-Khan Arana, Jean Sebastien Austin, Valerie Bourassa, Chengyang Wang, Valérie C Cabana, Calvin Wong, Kevin C Lister, Rose Rodrigues, Manon St-Louis, Marie-Eve Paquet, Michael C Carroll, Yaisa Andrews-Zwilling, Philippe Seguela, Artur Kania, Ted Yednock, Jeffrey S Mogil, Yves De Koninck, Luda Diatchenko, Arkady Khoutorsky, Alfredo Ribeiro-da-Silva.
      Activation of spinal microglia following peripheral nerve injury is a central component of neuropathic pain pathology. While the contributions of microglia-mediated immune and neurotrophic signalling have been well-characterized, the phagocytic and synaptic pruning roles of microglia in neuropathic pain remain less understood. Here, we show that peripheral nerve injury induces microglial engulfment of dorsal horn synapses, leading to a preferential loss of inhibitory synapses and a shift in the balance between inhibitory and excitatory synapse density. This synapse removal is dependent on the microglial complement-mediated synapse pruning pathway, as mice deficient in complement C3 and C4 do not exhibit synapse elimination. Furthermore, pharmacological inhibition of the complement protein C1q prevents dorsal horn inhibitory synapse loss and attenuates neuropathic pain. Therefore, these results demonstrate that the complement pathway promotes persistent pain hypersensitivity via microglia-mediated engulfment of dorsal horn synapses in the spinal cord, revealing C1q as a therapeutic target in neuropathic pain.
    DOI:  https://doi.org/10.1038/s41467-025-59849-1
  6. Nat Commun. 2025 May 17. 16(1): 4588
    A spatio-temporal brain miRNA expression atlas identifies sex-independent age-related microglial driven miR-155-5p increase.
    Annika Engel, Viktoria Wagner, Oliver Hahn, Aulden G Foltz, Micaiah Atkins, Amila Beganovic, Ian H Guldner, Nannan Lu, Aryaman Saksena, Ulrike Fischer, Nicole Ludwig, Eckart Meese, Tony Wyss-Coray, Andreas Keller.
      An in-depth understanding of the molecular processes composing aging is crucial to develop therapeutic approaches that decrease aging as a key risk factor for cognitive decline. Herein, we present a spatio-temporal brain atlas (15 different regions) of microRNA expression across the mouse lifespan (7 time points) and two aging interventions. MicroRNAs are promising therapeutic targets, as they silence genes by complementary base-pair binding of messenger RNAs and mediate aging speed. We first established sex- and brain-region-specific microRNA expression patterns in young adult samples. Then we focused on sex-dependent and independent brain-region-specific microRNA expression changes during aging. We identified three sex-independent brain aging microRNAs (miR-146a-5p, miR-155-5p, and miR-5100). For miR-155-5p, we showed that these expression changes are driven by aging microglia and target mTOR signaling pathway components and other cellular communication pathways. In this work, we identify strong sex-brain-region-specific aging microRNAs and microglial miR-155-5p as a promising therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-025-59860-6
  7. Neuron. 2025 May 14. pii: S0896-6273(25)00303-4. [Epub ahead of print]
    p16-expressing microglia and endothelial cells promote tauopathy and neurovascular abnormalities in PS19 mice.
    Sara I Graves, Charlton F Meyer, Karthik B Jeganathan, Darren J Baker.
      Cellular senescence is characterized by irreversible cell-cycle exit, a pro-inflammatory secretory phenotype, macromolecular damage, and deregulated metabolism. Senescent cells are highly associated with age-related diseases. We previously demonstrated that targeted elimination of senescent cells prevents neurodegenerative disease in tau (MAPTP301S;PS19) mutant mice. Here, we show that genetic ablation of the senescence mediator p16Ink4a is sufficient to attenuate senescence signatures in PS19 mice. Disease phenotypes-including neuroinflammation, phosphorylated tau, neurodegeneration, and cognitive impairment-were blunted in the absence of p16Ink4a. Additionally, we found that PS19 mouse brains display p16Ink4-dependent neurovascular alterations such as vessel dilation, increased vessel density, deregulated endothelial cell extracellular matrix, and astrocytic endfoot depolarization. Finally, we show that p16Ink4a deletion in endothelial cells and microglia alone attenuates many of the same phenotypes. Altogether, these results indicate that neurodegenerative disease in PS19 mice is driven, at least in part, by p16Ink4a-expressing endothelial cells and microglia.
    Keywords:  cellular senescence; endothelial cells; microglia; mouse model; neurodegeneration; p16(Ink4a); tauopathy
    DOI:  https://doi.org/10.1016/j.neuron.2025.04.020
  8. Neuron. 2025 May 19. pii: S0896-6273(25)00345-9. [Epub ahead of print]
    GADD45G operates as a pathological sensor orchestrating reactive gliosis and neurodegeneration.
    Tianjin Shen, Wenjiao Tai, Dongfang Jiang, Shuaipeng Ma, Xiaoling Zhong, Yuhua Zou, Chun-Li Zhang.
      Reactive gliosis is a hallmark of neuropathology and offers a potential target for addressing numerous neurological diseases. Here, we show that growth arrest and DNA damage inducible gamma (GADD45G), a stress sensor in astrocytes, is a nodal orchestrator of reactive gliosis and neurodegeneration. GADD45G expression in astrocytes is sufficient to incite astrogliosis, microgliosis, synapse loss, compromised animal behavior, and the aggravation of Alzheimer's disease (AD). Conversely, silencing GADD45G specifically in astrocytes preserves synapses and rescues the histological and behavioral phenotypes of AD. Mechanistically, GADD45G controls the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) and neuroimmune signaling pathways, including nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3), leading to profound molecular changes and the secretion of various factors that regulate both cell-autonomous and cell-nonautonomous reactive gliosis and glia-neuron interactions. These results uncover GADD45G signaling as a promising therapeutic target for AD and potentially for numerous other neurological disorders.
    Keywords:  Alzheimer’s disease; GADD45G; IRF3; MAP3K4; NF-κB; astrocytes; glia-neuron interactions; microglia; reactive gliosis; synapse loss
    DOI:  https://doi.org/10.1016/j.neuron.2025.04.033
  9. Adv Sci (Weinh). 2025 May 23. e03389
    Mechanotransduction Activates Microglia and Impairs Phagocytosis in Stiff Amyloid-β Plaques.
    Yulin Liu, Junjie Zhang, Yuxiang Zhao, Feixiang Fang, Siyu Zhang, Qiqi An, Jian Zhuang, Feng Xu, Fei Li.
      In Alzheimer's disease (AD), microglia are activated by mechanical and biochemical cues in the amyloid-β (Aβ) plaque-associated microenvironment, causing neuroinflammation. While the impact of Aβ stiffness on microglial activation and the dynamic interplay between inflammation and phagocytosis remain unclear. Here, an in vitro Aβ plaque-associated microglia microenvironment model is built and investigated how the stiffness of Aβ plaques triggers microglial activation via the PIEZO1 mechanotransduction pathway. Scanning electrochemical microscopy and scanning ion conductance microscopy are employed to in situ monitor reactive oxygen species release, membrane permeability, and phagocytic activity of microglia. It is found that Aβ stiffness drives early microglial activation, forming an oxidative-stressed microenvironment that impairs the membrane integrity of microglia. And the antioxidant-resveratrol effectively improves the phagocytosis dysfunction of the impaired microglia. This work reveals the complex interplay among mechanical cues, neuroinflammation, and phagocytic dysfunction in microglia and suggests potential therapeutic strategies targeting microglial dysfunction in AD.
    Keywords:  Alzheimer's disease (AD); amyloid‐β (Aβ) plaques‐associated microenvironment; microglia; scanning electrochemical microscopy (SECM); scanning ion conductance microscopy (SICM)
    DOI:  https://doi.org/10.1002/advs.202503389
  10. Adv Sci (Weinh). 2025 May 21. e2400747
    Immune Checkpoint PD-L1 Modulates Retinal Microglial Activation to Alleviate Vascular Leakage in Choroidal Neovascularization via ERK.
    Yue Zou, Junliang Jiang, Yunqin Li, Xinyi Ding, Qiuping Tong, Ying Shi, Lei Xiao, Ling Chen.
      Neovascular age-related macular degeneration (NVAMD) is a common retinal disease causing vision loss in the elderly. Neuroinflammation significantly contributes to NVAMD's etiology. This study explores the role of Programmed cell death ligand 1 (PD-L1), an immune checkpoint (ICP) in microglia, known for limiting neuroinflammation in neurodegenerative diseases, and its potential function in NVAMD. This work finds increased PD-L1 expression in retinal microglia following laser injury. PD-L1 knockout (KO) or inhibitory PD-L1 antibody treatment worsens vascular leakage and neoangiogenesis in a laser-induced NVAMD mouse model, effects reversible by microglia depletion with PLX5622. This study underscores that choroidal neovascularization (CNV) may be regulated by multiple mechanisms, with PD-L1 modulation representing one of these pathways. Blocking PD-L1 elevated proinflammatory factors and p-ERK levels, indicating microglial overactivation in NVAMD. Conversely, enhancing PD-L1 signaling reduced neuroinflammation and neovascularization via ERK. These findings highlight PD-L1's role in neoangiogenesis and neuroinflammation in NVAMD, suggesting its potential as a target for immunomodulatory treatment in NVAMD.
    Keywords:  microglia/macrophage; neovascular age‐related macular degeneration; neuroinflammation, PD‐L1
    DOI:  https://doi.org/10.1002/advs.202400747
  11. Brain Behav Immun. 2025 May 17. pii: S0889-1591(25)00193-X. [Epub ahead of print]
    SORLA Orchestrates microglial dynamics for enhanced neuroprotection and recovery following ischemic stroke.
    Sehui Ma, Tongmei Zhang, Junkai Lv, Shiqi Liang, Shuaizhu Zhao, Xinyue Nan, Ziyue Dou, Jun Yang, Youming Lu, Rong Liu, Hao Li.
      This study identifies a novel function of Sortilin-related receptor with A-type repeats (SORLA), traditionally linked to Alzheimer's Disease (AD) as a high-risk gene and associated with neuronal function, in modulating microglial responses to ischemic stroke. We discovered that SORLA expression is significantly reduced in microglia following stroke, a change linked to increased brain injury and diminished neurological recovery. Utilizing SORLA knockout and overexpression models, we demonstrated its essential role in adjusting microglial inflammatory responses. Notably, microglial-specific overexpression of SORLA not only promoted anti-inflammatory actions and effective phagocytosis but also surpassed traditional concepts of microglial polarization. This overexpression mitigated brain damage and enhanced neurofunctional recovery post-stroke, highlighting the neuroprotective potential of SORLA. This breakthrough challenges the prevailing understanding the role of SORLA and opens new therapeutic possibilities for stroke recovery, indicating its wider relevance for neurodegenerative disease management.
    Keywords:  Inflammatory; Microglia; Neuroprotection; SORLA; Stroke
    DOI:  https://doi.org/10.1016/j.bbi.2025.05.016
  12. Brain Behav Immun. 2025 May 20. pii: S0889-1591(25)00197-7. [Epub ahead of print]
    Intravenous SARS-CoV-2 Spike protein induces neuroinflammation and alpha-synuclein accumulation in brain regions relevant to Parkinson's disease.
    Cara Sophie Schreiber, Lucas Navarro Ramil, Juliette Bieligk, Robert Meineke, Christopher Käufer, Franziska Richter.
       BACKGROUND: Coronavirus disease 2019 (COVID-19) frequently presents with neurological symptoms in human patients and leads to long-lasting brain pathology in a hamster model. There is no overt SARS-CoV-2 virus replication in central neurons. Whether viral proteins are sufficient to cause this pathology requires further investigations. The SARS-CoV-2 Spike-protein S1-subunit (S1-protein) has recently gained interest for causing neuroinflammation and accelerating aggregation of alpha-synuclein (aSyn) in vitro. Here, we show the impact of S1-protein in a broad spectrum of brain regions after injection via three different application routes in C57/BL6 mice.
    METHODS: S1-protein was administered either intranasally, intravenously or intracerebrally. We quantified aSyn immunoreactivity and phosphorylated aSyn (pS129), microglia and astrocyte reactivity, ACE2/Neuropilin-1 receptor expression, and parvalbumin-positive interneurons in limbic system, basal ganglia, and cortical regions 14 days post-application. Plasma cytokine profiles were assessed 6 days post-injection.
    RESULTS: While intracerebral injection resulted in decreased aSyn immunoreactivity with increased pS129 in males, intravenous injection led to increased levels of aSyn immunoreactivity and microglia cell density, predominantly in brain regions associated with Parkinson's disease pathology. Intranasal application of S1-protein induced microgliosis in some brain regions but resulted in sex-dependent alterations of aSyn levels, with increases in females and decreases in males. All routes showed sex-dependent alterations in astrocytic reactivity, receptor expression, and parvalbumin-positive interneurons.
    CONCLUSION: Our results demonstrate that S1-protein itself leads to neuroinflammation, altered aSyn homeostasis, and disruption of inhibitory circuits in a route- and sex-dependent manner. These findings indicate the possibility of S1-protein being a crucial agent for both neuroinflammatory processes and altered protein regulation mechanisms. S1-protein trapped in tissue reservoirs could therefore explain symptoms occurring or persisting beyond viral clearance (Post COVID-19 condition).
    Keywords:  Long-COVID; Neurodegenerative disease; Neuroinflammation; Neurological symptoms; S1-protein
    DOI:  https://doi.org/10.1016/j.bbi.2025.05.021
  13. Cell Death Differ. 2025 May 21.
    NLRX1 mediated impaired microglial phagocytosis of NETs in cerebral ischemia and reperfusion injury.
    Jialing Peng, Yuxin Huang, Tengjing He, Yang Zhan, Jun Liu.
      Ischemic stroke is one of the common causes of disability and death, and subsequent pathological processes consequent to revascularization could promote secondary tissue damage leading to neuronal death, namely cerebral ischemia and reperfusion injury. Neutrophils could invade injured brain parenchyma after vascularization and exert neurotoxicity by forming neutrophil extracellular traps (NETs). However, unwanted NETs were accumulated in the infarcted core of transient middle cerebral artery occlusion (tMCAO) rats and the mechanism is unknown. Efficient microglial phagocytosis is crucial for the homeostasis of cerebral parenchyma after stroke, and dysfunction of microglial phagocytosis of NETs were observed in the infarcted core cortex at tMCAO 1 d and the accumulation of NETs persisted to 7 d, which exerting deleterious neuronal damage after stroke. However, the detailed mechanisms underlying the dysfunction of microglial phagocytosis of NETs remained unclear. Our results further demonstrated that NLRX1 was mainly enhanced in the microglial cells in the infarcted core cortex at tMCAO 1 d and promoted galectin-3 expression on the lysosomes, facilitating the lysosomal dysfunction and impaired microglial phagocytosis via mTOR/TFEB signaling. NLRX1-silencing was able to suppress the galectin-3 intensity, inhibit the phosphorylation of mTOR and facilitate the nuclear localization of TFEB, ameliorating the lysosomal dysfunction and microglial phagocytosis of NETs. Our results uncovered the regulation of NLRX1 in the dysfunctional microglial phagocytosis of NETs and provided insights into the therapeutic potential for targeting at microglial lysosomal function in cerebral ischemia and reperfusion injury.
    DOI:  https://doi.org/10.1038/s41418-025-01526-3
  14. Proc Natl Acad Sci U S A. 2025 May 27. 122(21): e2501527122
    Loss of insulin signaling in microglia impairs cellular uptake of Aβ and neuroinflammatory response exacerbating AD-like neuropathology.
    Wenqiang Chen, Xiangyu Liu, Vitor Rosetto Muñoz, C Ronald Kahn.
      Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimer's disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in the brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprogramming with an increase in glycolysis and impaired uptake of Aβ. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of Aβ plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism and the ability of the cells to take up Aβ, such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together, these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.
    Keywords:  Alzheimer’s disease; insulin; metabolism; microglia; neuroinflammation
    DOI:  https://doi.org/10.1073/pnas.2501527122
  15. Proc Natl Acad Sci U S A. 2025 May 27. 122(21): e2414316122
    Imaging a concussion and the ensuing immune response at the blood-brain barrier.
    Rita H Nguyen, Michelle Newton, Rachel M Kratofil, Brittney N V Scott, Fernanda Castanheira, Jung-Seok Kim, Florent Ginhoux, Steffen Jung, Paul Kubes.
      Concussions can cause debilitating symptoms despite no evidence of structural changes on diagnostic imaging. The cellular events occurring in the brain parenchyma following concussion, especially repetitive concussion, are not well elucidated. We developed a concussion model to induce a confined area of injury without causing frank hemorrhage. Using intravital microscopy, we observe activation of the vasculature that supported neutrophil rolling and platelet adhesion but no overt cellular recruitment from blood into brain parenchyma. Activated resident, not monocyte-derived, macrophages relocated to the injury site via Cx3cr1 and phagocytosed dysfunctional/detached astrocytes via scavenger receptors and TLR4, particularly after repetitive concussion. Additionally, microglia sealed areas of blood-brain barrier (BBB) disruption via purinergic pathways. Using a splitCre approach to dissect microglia and perivascular macrophages, we show that microglial invasion into the injury site is key to reducing BBB disruption. Our data suggest that microglia repair the BBB following concussion, but in doing so significantly alter the cellular ultrastructure of the brain milieu.
    Keywords:  astrocytes; blood–brain barrier; concussion; microglia; traumatic brain injury
    DOI:  https://doi.org/10.1073/pnas.2414316122
  16. J Neuroinflammation. 2025 May 21. 22(1): 136
    Microglial dynamics and neuroinflammation in prodromal and early Parkinson's disease.
    Frida Lind-Holm Mogensen, Philip Seibler, Anne Grünewald, Alessandro Michelucci.
      Parkinson's disease (PD) is characterized by a drastic loss of dopaminergic neurons already at diagnosis. As this loss of neurons starts decades before diagnosis, understanding the prodromal stages of the disease might offer novel strategies to curb its progression. While the precise pathogenic mechanisms underlying PD remain incompletely understood, growing evidence suggests that neuroinflammation and immune dysregulation play a central role in the development and progression of the disease. Here, we delve into the emerging roles of microglia, the resident immune cells of the central nervous system, in the pathogenesis of prodromal and early-stage PD. We emphasize that microglia contribute to neuroinflammation, protein aggregation and neurodegeneration, although the underlying mechanisms are not yet known. Neuroimaging studies have provided valuable insights into the patterns of microglial activation detected in individuals with prodromal PD and at the time of clinical diagnosis. Furthermore, we highlight the complex interplay between immune dysregulation and neurodegeneration along PD development, including alterations in the peripheral immune system, brain-gut interactions and brain-immune interfaces. Lastly, we outline existing models for investigating microglial involvement in prodromal PD, along with the impact of anti-inflammatory therapies and strategies to modify risk factors. In conclusion, targeting microglial activation and immune dysfunctions in individuals at risk of PD could represent a promising preventive measure and may offer novel therapeutic strategies for early intervention and disease modification.
    Keywords:  Microglia; Neuroinflammation; Parkinson’s disease; Prodromal stage; REM-sleep behaviour disorder
    DOI:  https://doi.org/10.1186/s12974-025-03462-y
  17. J Neuroinflammation. 2025 May 17. 22(1): 132
    Rebamipide (Mucosta®), a clinically approved drug, alleviates neuroinflammation and dopaminergic neurodegeneration in a Parkinson's disease model.
    Hye-Sun Lim, Jinyoung Park, Eunjeong Kim, Wonhwa Lee, Hwi-Yeol Yun, Seung Hoon Lee, Gunhyuk Park.
       BACKGROUND: Parkinson's disease (PD) is characterized by dopaminergic neuron loss, neuroinflammation, and motor dysfunction. PD is a multifactorial disease, with neuroinflammation driven by NLRP3 inflammasome activation representing an important component of its pathological progression. Therefore, we aimed to evaluate the therapeutic potential of rebamipide (Mucosta®), a clinically approved anti-inflammatory agent, in PD by targeting the NLRP3 inflammasome. Specifically, we examined the effects of rebamipide on neuroinflammation, dopaminergic neuron preservation, and motor deficits using BV2 microglia cells and a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model.
    MAIN BODY: Rebamipide alleviated microglial activation and downstream neuroinflammation by suppressing the NLRP3-NEK7 interaction, resulting in dopaminergic neuron protection in the MPTP-induced PD model. Rebamipide downregulated IL-1β levels in BV2 microglia cells treated with α-synuclein and MPP+. Molecular docking analysis revealed a high binding affinity between rebamipide and the NLRP3-NEK7 interaction interface. Surface plasmon resonance analysis confirmed the direct binding of rebamipide to NLRP3, with notable kinetic affinity, supporting its role as a novel NLRP3 inflammasome inhibitor. Rebamipide significantly downregulated IL-1β levels, microglial activation, and dopaminergic neuron loss in the MPTP mouse model by disrupting inflammasome activation. Rebamipide preserved dopamine levels in the striatum and improved motor deficits, including bradykinesia and motor coordination. The neuroprotective effects of rebamipide were neutralized in NLRP3 knockout mice, confirming the dependency of its action on NLRP3.
    CONCLUSION: Considering its established clinical use, this study supports repurposing rebamipide for treating PD and other NLRP3 inflammasome-driven neuroinflammatory diseases.
    Keywords:  MPTP; NLRP3 inflammasome; Neuroinflammation; Parkinson’s disease; Rebamipide
    DOI:  https://doi.org/10.1186/s12974-025-03461-z
  18. J Neuroinflammation. 2025 May 21. 22(1): 134
    Caveolin-1 negatively regulates the calcitonin receptor-like receptor and neuroinflammation in a female mouse model of migraine.
    Yanjie Zhou, Wu Chen, Yu Zhang, Liu Yang, Fu Lu, Wen Yan, Qingfang Xie, Ying Huang, Wanbin Huang, Lintao Wang, Ziming Zeng, Zheman Xiao.
       BACKGROUND: Caveolin-1 (CAV1), a scaffolding protein critical for caveolae formation, regulates G-protein-coupled receptor (GPCR) signaling via caveolae-mediated endocytosis. The calcitonin receptor-like receptor (CLR), a GPCR and core subunit of the calcitonin gene-related peptide (CGRP) receptor, is a therapeutic target for migraine. However, the role of CAV1 in CLR regulation and migraine remains unclear.
    METHODS: A migraine model was established in female mice via dural inflammatory soup (IS) application. Migraine-like behaviors were assessed using Von Frey filament, spontaneous pain behavior counts, light/dark box, and acetone test. CAV1 was overexpressed by lentivirus and downregulated by small interfering RNA (siRNA) technology. Methyl-β-cyclodextrin (MβCD) was used to inhibit caveolae-mediated endocytosis. The molecular mechanism of CAV1 on CLR and neuroinflammation was investigated using biochemistry, multiplex immunohistochemistry staining, internalization assay, and co-immunoprecipitation.
    RESULTS: Repeated IS stimulation elevated CLR expression and internalization in the trigeminal nucleus caudalis (TNC), concurrently activating ERK/CREB signaling, promoting microglial activation, and increasing inflammatory cytokines (TNFα, IL-1β). CAV1 directly interacted with CLR, promoting its degradation. CAV1 knockdown in the TNC exacerbated migraine pathology, characterized by CLR accumulation, enhanced ERK/CREB phosphorylation, and amplified neuroinflammation. Conversely, CAV1 overexpression or MβCD-mediated caveolae disruption normalized CLR levels, reduced signaling hyperactivity, and reversed nociceptive behaviors.
    CONCLUSION: CAV1 negatively regulates CLR stability, suppressing ERK/CREB signaling and microglial inflammation in a preclinical female migraine model. These findings suggest that CAV1 contributes to migraine-related hyperalgesia and may represent a novel therapeutic target for migraine treatment.
    Keywords:  CLR; Caveolin-1; Microglia; Migraine; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12974-025-03466-8
  19. Cell Rep. 2025 May 15. pii: S2211-1247(25)00488-7. [Epub ahead of print]44(5): 115717
    Optogenetic activation of cortical microglia promotes neuronal activity and pain hypersensitivity.
    Min-Hee Yi, Yi Liu, Yong U Liu, Jinkyung Lee, Priyanka Hanumaihgari, Sebastian Parusel, Dale B Bosco, Lingxiao Wang, Jiaying Zheng, Wu Shi, Lattawat Eauchai, Supin Chompoopong, Christine L Hunt, Long-Jun Wu.
      Chronic pain following peripheral nerve injury is accompanied by increased neuronal activity in the somatosensory cortex. However, whether and how cortical microglia contribute to these changes is less understood. To this end, we applied an optogenetic strategy to specifically target cortical microglia and investigate their function in behavioral pain sensitization. We found that optogenetic activation of microglia in the primary somatosensory cortex (S1) via red-activated channelrhodopsin (ReaChR) triggered pain hypersensitivity and affective-motivational responses in mice. Remarkably, S1-targeted optogenetic stimulation increased microglial landscape changes and ATP release. In addition, optogenetic stimulation altered the microglial proteomic profile, upregulated neuronal c-Fos expression, and enhanced neuronal Ca2+ signaling in the S1. Our results provide mechanistic evidence linking cortical microglia with neuronal hyperactivity and chronic pain behaviors.
    Keywords:  ATP; CP: Neuroscience; ReaChR; chronic pain; microglia; microglial landscape change; optogenetics; somatosensory cortex; two-photon imaging
    DOI:  https://doi.org/10.1016/j.celrep.2025.115717
  20. Elife. 2025 May 21. pii: RP96693. [Epub ahead of print]13
    Modeling hereditary diffuse leukoencephalopathy with axonal spheroids using microglia-sufficient brain organoids.
    Wei Jie Wong, Yi Wen Zhu, Hai Ting Wang, Jia Wen Qian, Ziyi Li, Song Li, Zhao Yuan Liu, Wei Guo, Shuang Yan Zhang, Bing Su, Fang Ping He, Kang Wang, Florent Ginhoux.
      Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare, fatal, adult-onset neurodegenerative disease that is most often caused by mutations affecting the colony stimulating factor-1 receptor (CSF-1R). To understand how CSF-1R-mutation affects human microglia - the specialized brain-resident macrophages of the central nervous system - and the downstream consequences for neuronal cells, we used a macrophage and forebrain organoid co-culture system based on induced pluripotent stem cells generated from two patients with HDLS, with CSF-1R gene-corrected isogenic organoids as controls. Macrophages derived from iPSC (iMacs) of patients exhibited a metabolic shift toward the glycolytic pathway and reduced CSF-1 sensitivity, which was associated with higher levels of IL-1β production and an activated inflammatory phenotype. Bulk RNA sequencing revealed that iMacs adopt a reactive state that leads to impaired regulation of neuronal cell populations in organoid cultures, thereby identifying microglial dysregulation and specifically IL-1β production as key contributors to the degenerative neuro-environment in HDLS.
    Keywords:  CSF1R; HDLS; human; immunology; inflammation; macrophage; microglia; organoid
    DOI:  https://doi.org/10.7554/eLife.96693
  21. Elife. 2025 May 19. pii: RP101630. [Epub ahead of print]13
    MorphoCellSorter is an Andrews plot-based sorting approach to rank microglia according to their morphological features.
    Sarah Benkeder, Son-Michel Dinh, Paul Marchal, Priscille De Gea, Muriel Thoby-Brisson, Violaine Hubert, Ines Hristovska, Gabriel Pitollat, Kassandre Combet, Laura Cardoit, Bruno Pillot, Christelle Leon, Marlene Wiart, Serge Marthy, Jérôme Honnorat, Olivier Pascual, Jean-Christophe Comte.
      Microglia exhibit diverse morphologies reflecting environmental conditions, maturity, or functional states. Thus, morphological characterization provides important information to understand microglial roles and functions. Most recent morphological analysis relies on classifying cells based on morphological parameters. However, this classification may lack biological relevance, as microglial morphologies represent a continuum rather than distinct, separate groups, and do not correspond to mathematically defined clusters irrelevant of microglial cells function. Instead, we propose a new open-source tool, MorphoCellSorter, which assesses microglial morphology by automatically computing morphological criteria, using principal component analysis and Andrews plots to score cells. MorphoCellSorter properly ranked cells from various microglia datasets in mice and rats of different ages, from in vivo, in vitro, and ex vivo models, that were acquired using diverse imaging techniques. This approach allowed for the discrimination of cell populations in various pathophysiological conditions. Finally, MorphoCellSorter offers a versatile, easy, and ready-to-use method to evaluate microglial morphological diversity that could easily be generalized to standardize practices across laboratories.
    Keywords:  computational biology; human; mouse; neuroscience; rat; rodent; systems biology; vertebrate
    DOI:  https://doi.org/10.7554/eLife.101630
  22. Front Immunol. 2025 ;16 1558842
    Role of lncRNA Xist-miR-124-CCL2 axis in HIV Tat-mediated microglial activation and neuroinflammation.
    Palsamy Periyasamy, Seema Singh, Abiola Oladapo, Muthukumar Kannan, Shilpa Buch.
       Introduction: HIV proteins, such as the Transactivator of transcription (Tat), mediate neuroinflammation in the central nervous system by promoting the release of pro-inflammatory cytokines and chemokines. Long noncoding RNAs (lncRNAs) regulate gene expression by sponging microRNAs (miRs), but their role in HIV Tat-mediated microglial activation remains poorly understood. This study aimed to investigate the involvement of the lncRNA Xist-miR-124-CCL2 axis in HIV Tat-exposed microglial cells.
    Methods: Mouse primary microglial cells were exposed to HIV Tat, and the expression of lncRNA Xist, miR-124, and CCL2 was evaluated using qPCR, Western blotting, and ELISA. Dual-luciferase reporter and Argonaute immunoprecipitation assays were used to confirm molecular interactions. Functional experiments involved lncRNA Xist silencing and miR-124 overexpression. In vivo validation was performed using doxycycline-inducible HIV Tat transgenic mice.
    Results: HIV Tat significantly upregulated lncRNA Xist and downregulated miR-124 expression in mouse primary microglial cells. miR-124 was identified as a direct target of lncRNA Xist and the 3'-UTR of CCL2. Silencing lncRNA Xist or overexpressing miR-124 reduced HIV Tat-induced CCL2 expression and microglial activation. In vivo studies corroborated these findings, with doxycycline-fed iTat mice showing elevated lncRNA Xist and CCL2 levels and reduced miR-124 expression in the frontal cortex.
    Discussion: Our findings identify a novel regulatory axis whereby HIV Tat-induced upregulation of lncRNA Xist sponges miR-124, leading to CCL2 overexpression and microglial activation. Targeting the lncRNA Xist-miR-124-CCL2 pathway may represent a promising therapeutic strategy to mitigate neuroinflammation associated with NeuroHIV.
    Keywords:  CCL2; HIV Tat; lncRNA Xist; miR-124; microglia; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2025.1558842
  23. Int Immunopharmacol. 2025 May 18. pii: S1567-5769(25)00879-3. [Epub ahead of print]158 114889
    Betulinic acid enhances autopahgy to promote microglial M2 polarization and alleviate inflammation via AMPK-HDAC5-KLF2 signaling pathways in spinal cord injury.
    Zili He, Yitie Xu, Yu Zhang, Mengqi Jin, Yinuo Sun, Fangying Tang, Chuangqi Qiu, Abass Mashud Akinfemi Junior, Yunhao Cai, Xiaodan Xu, Xianghang Chen, Kongbin Chen, Guangheng Xiang, Jian Xiao, Jian Wang, Jing Wang, Baoyi Chen.
      Spinal cord injury (SCI) leads to neuroinflammation and activates microglia, which are crucial contributors to neurological deficits. Betulinic acid (BA), a naturally occurring pentacyclic triterpenoid, has demonstrated effectiveness in treating inflammatory and neurological disorders. This study aims to explore the potential role and underlying mechanism of BA in modulating microglial activation and inflammation in the context of SCI. Using a mouse SCI model, we assessed motor recovery via Basso Mouse Scale (BMS) and neuronal survival via H&E/Nissl staining. Western blotting, qPCR, immunofluorescence, and flow cytometry were employed to analyze microglial polarization, autophagy, and AMPK-HDAC5-KLF2 signaling in vivo and in LPS-stimulated BV2 cells. Our findings reveal that BA significantly enhances functional recovery and reduces neuronal apoptosis following SCI. Furthermore, BA facilitates the phenotypic transition of microglia from the M1 to M2 phenotype, thereby decreasing inflammatory factors in both the SCI model and LPS-stimulated BV2 cells. BA treatment restores the disrupted autophagy flux in microglia induced by SCI or LPS, which in turn mitigates M1 polarization and inflammation. Mechanistically, BA restores autophagy flux by activating the AMPK-HDAC5-KLF2 axis, thereby shifting microglia from pro-inflammatory M1 to anti-inflammatory M2 phenotype.
    Keywords:  Autophagy; Betulinic acid; Kruppel-like factor 2; Microglia; Neuroinflammation; Polarization; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.intimp.2025.114889
  24. CNS Neurosci Ther. 2025 May;31(5): e70406
    11,12-Diacetyl-Carnosol Ameliorates Depression-Like Behaviors and Memory Dysfunction in CUMS Mouse Model via Inhibiting HMGB1-Mediated Neuroinflammation.
    Kunying Zhao, Lirong Xiang, Shuda Yang, Xinglong Chen, Xiaomi Yang, Junfang Dong, Shangpeng Wu, Si Yang, Min Zhang, Weiyan Hu.
       BACKGROUNDS: 11,12-Diacetyl-carnosol (DACA), a derivative of carnosol, exhibits significant anti-inflammatory and antioxidant properties. However, its antidepressant effects and underlying mechanisms remain unclear. High mobility group box 1 protein (HMGB1)-mediated inflammatory responses and associated neurofunctional impairments play a crucial role in the pathogenesis of depression. This study aimed to investigate whether DACA exerts anti-inflammatory and antidepressant effects and whether its mechanisms involve the HMGB1/NF-κB/NLRP3 signaling pathway.
    METHODS: (1) A depression model was established in mice through 6 weeks of chronic unpredictable mild stress (CUMS). From the 4th week of stimulation, the treatment group received DACA for 3 weeks. (2) BV2 cells were stimulated with LPS+ATP, and the treatment group was cultured in DACA medium for 24 h. (3) Supernatants from BV2 cells were used to culture primary neurons. To confirm the critical role of HMGB1 in DACA's antidepressant effects, CUMS-stressed mice were treated with glycyrrhizin (GZA) or the DACA+GZA combination. Depressive-like behaviors were evaluated using the sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), forced swim test (FST), and Morris water maze (MWM). Hippocampal microglial cell and primary neuron morphology were assessed by immunofluorescence, and dendritic spine density in hippocampal neurons was examined using Golgi staining. IL-6 and TNF-α concentrations in mouse serum and BV2 supernatant were measured by ELISA. Western blotting was used to detect protein expressions of HMGB1, NF-κB p65, p-NF-κB p65, NLRP3, and IL-1β in the hippocampus and BV2 cells.
    RESULTS: CUMS-exposed mice showed decreased sucrose preference, increased immobility in TST and FST, prolonged escape latency in MWM, and reduced crossings. Microglial activation and upregulation of HMGB1, NF-κB p65, p-NF-κB p65, NLRP3, and IL-1β were observed in both CUMS-stressed mice and LPS+ATP-induced BV2 cells, with reduced dendritic spine density in the hippocampus. DACA significantly reversed these phenomena. The effects of DACA were comparable to those of GZA treatment, and no changes were observed with the DACA+GZA combination.
    CONCLUSION: The HMGB1/NF-κB/NLRP3 signaling pathway is involved in DACA's therapeutic effects on depression.
    Keywords:  DACA; HMGB1; depression; microglia; neuroinflammation
    DOI:  https://doi.org/10.1111/cns.70406
  25. Glia. 2025 May 22.
    Mapping Glial Autophagy Dynamics in an Amyotrophic Lateral Sclerosis Mouse Model Reveals Microglia and Astrocyte Autophagy Dysfunction.
    Nirma D Perera, Subhavi De Silva, Doris Tomas, Brittany Cuic, Bradley J Turner.
      Amyotrophic lateral sclerosis (ALS) is defined by motor neuron death. However, recent research has identified non-cell-autonomous mechanisms, with significant involvement of glia in disease progression. We link previous observations of intracellular protein aggregates in glia to the autophagy pathway, the primary mediator of intracellular degradation of large protein aggregates. While dysfunctional autophagy is reported in ALS motor neurons, pre-clinical and clinical outcomes of autophagy modulators have been inconsistent, indicating the need for a nuanced understanding of autophagy dynamics across CNS cell types and ALS-affected regions. We hypothesized that glial autophagy is defective in ALS, with glial-type-specific dysfunction. To investigate in vivo autophagy dynamics, we intercrossed SOD1G93A mice with transgenic RFP-EGFP-LC3 autophagy reporter mice, enabling the quantification of autophagy degradation, termed flux. Investigation of autophagy dynamics in SOD1 oligodendrocytes, microglia, and astrocytes at key disease stages uncovered useful insights. While oligodendrocytes seemed to mount effective compensatory autophagic responses to combat mutant SOD1, significantly increased autophagy flux was observed in symptomatic spinal microglia and astrocytes in comparison to controls. Symptomatic SOD1 astrocytes displayed greater autophagy dysfunction compared to microglia, with subcellular analysis revealing cell compartment-specific, transient autophagy defects that returned to control levels by end stage. Interestingly, spinal glia showed more pronounced and earlier autophagy dysfunction compared to motor cortex glia, where autophagy dysfunction emerged later in disease end stage, aligning with greater spinal cord pathology reported in this model. Our results suggest that cell-type- and time-specific targeting might be essential when developing autophagy therapeutics for ALS, with prioritization of astrocytic autophagy modulation.
    Keywords:  ALS; SOD1; SOD1G93A; astrocytes; autophagy; microglia; oligodendrocytes
    DOI:  https://doi.org/10.1002/glia.70045
  26. Glia. 2025 May 23.
    Pathways to Progressive Disability in Multiple Sclerosis: The Role of Glial Cells in Chronic CNS Inflammation.
    Volker Siffrin.
      Multiple sclerosis (MS) is the most common non-infectious inflammatory CNS disease, characterized by progressive neurodegeneration and focal demyelinated lesions. Traditionally considered an autoimmune disease, MS is driven by the immune system's attack on CNS myelin, resulting in cumulative disability. However, conventional anti-inflammatory treatments often fail to prevent progressive deterioration, particularly in the absence of overt inflammation, highlighting the need for a deeper understanding of its pathogenesis. Recent research has revealed a more complex disease mechanism involving both peripheral immune responses and intrinsic CNS factors, with glial cells playing a central role. Persistent inflammation in MS is associated with mixed active/inactive lesions dominated by microglia and astrocyte dysregulation. These glial populations exhibit maladaptive activation, contributing to failed remyelination and ongoing neurodegeneration. Transcriptomic and epigenomic alterations as well as aging further exacerbate glial dysfunction, creating a self-perpetuating cycle of inflammation and damage. Emerging evidence suggests that the interplay between peripheral immune cells and glial populations and the potential dual-use nature of molecular tools shared by the immune system and CNS disrupts homeostatic signaling, leading to a loss of tissue integrity. This review synthesizes findings on glial cell biology in MS, with a focus on microglia and astrocytes, while addressing their roles in demyelination, synapse loss, and neurodegeneration. The limitations of animal models, particularly EAE, in replicating the complexity of MS are also addressed. Finally, critical questions are outlined to guide future research into glial pathology and to identify novel therapeutic approaches targeting progressive MS.
    Keywords:  CNS pathology; astrocytes; chronic inflammation; glial cells; microglia; multiple sclerosis; neurodegeneration; remyelination
    DOI:  https://doi.org/10.1002/glia.70044
  27. J Neurosci. 2025 May 22. pii: e1322242025. [Epub ahead of print]
    Microglia supports both the singular form of LTP expressed by the lateral perforant path and episodic memory.
    J Chavez, A A Le, J Quintanilla, J C Lauterborn, Y Jia, A M Tagne, H L Lee, K M Jung, D Piomelli, G Lynch, C M Gall.
      We report here that microglia exert a surprisingly discrete but functionally critical influence on synaptic plasticity in mouse hippocampus. Treatment of adult male mice with colony stimulating factor 1 receptor antagonist PLX5622 (PLX), with resultant depletion of forebrain microglia, did not disturb basal synaptic transmission at four synaptic connections in hippocampus. Long-term potentiation (LTP) was also intact for three of these sites, but the singular, endocannabinoid-dependent form of LTP expressed by lateral perforant path (LPP) input to the dentate gyrus (DG) was severely impaired. The LPP-LTP defect occurred in conjunction with a pronounced increase in DG (but not neocortical) levels of 2-arachidonoylglycerol (2-AG), the retrograde (spine-to-terminal) endocannabinoid messenger that initiates LPP-LTP. Despite this, concentrations of the 2-AG synthetic enzyme diacylglycerol lipase were not affected by PLX treatment. Synaptic levels of the cannabinoid type 1 receptor, which mediates 2-AG effects on LPP-LTP, were similarly unaffected. Prior work has implicated the LPP in episodic memory. We determined that the LPP-LTP impairment in PLX-treated mice was accompanied by a failure to acquire the three basic elements of an episode: the identities, locations, and presentation order for a collection of olfactory cues. Treatment with JZL184, which inhibits the 2-AG degradative enzyme monoglyceride lipase, restored both LPP-LTP and episodic 'What' encoding in PLX-treated mice. We conclude that microglia selectively regulate endocannabinoid transmission at the LPP-DG synapse and thereby potently influence synaptic plasticity at the initial stage of a cortico-hippocampal circuit that is critical for episodic memory.Significance Statement There has been considerable interest in microglial involvement in the moment-to-moment operations of the brain. However, the present studies show that, with one prominent exception, treatments that significantly deplete forebrain microglia have no detectable influence on synaptic operations at multiple sites within hippocampus. Nevertheless, long-term potentiation was selectively disrupted within the lateral perforant path, a primary cortical input to hippocampus. Relatedly, microglial depletion was associated with severe impairments in encoding the principal components of episodic memory. These results indicate microglial influences on synaptic transmission are surprising discrete and yet essential for orderly cognition.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1322-24.2025
  28. Sci Rep. 2025 May 22. 15(1): 17760
    Single-cell sequencing and transcriptomic data reveal that P65 activation significantly promotes microglia-mediated neuroinflammation after ischemic stroke.
    Ruiyu Wang, Yilun Qian, Xinchen Zhou, Hang Xu, Yu Wang, Yao Geng, Tianshu Wang, Binxiu Sha.
      The pathophysiological mechanisms underlying cerebral ischemia-reperfusion (I/R) injury are highly complex. Previous studies have indicated phenotypic changes in various cell types following stroke but have failed to identify the key regulatory genes and cell subtypes associated with the disease. The study utilized five datasets: GSE227651, GSE104036, GSE116878, GSE249957, and GSE22255. The Seurat pipeline was employed for standard quality control and single-cell data analysis. Monocle2 and CytoTRACE were used for trajectory analysis, while Mfuzz was applied to identify time-series gene expression patterns. Middle cerebral artery occlusion (MCAO) mice served as the animal model for cerebral I/R injury, and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated BV2 cells were used to simulate microglial phenotypic changes following ischemia-reperfusion. qPCR, Western blotting, and immunofluorescence staining were used to detect key gene and protein alterations. P65 was identified as a key transcription factor driving inflammatory responses and transcriptional changes following ischemic stroke. Two microglial subtypes, Cx3cr1 + and Cdk1+, were identified, with their proportions significantly increasing on days 1 and 3 after MCAO. Increased levels of inflammation, neuronal apoptosis, and P65 phosphorylation in microglia were observed in both the MCAO animal model and OGD/R cell model. Notably, inhibition of P65 phosphorylation effectively suppressed the progression of inflammation during cerebral I/R injury. We identified microglial subtypes associated with inflammatory responses following cerebral ischemia-reperfusion injury, with their proportions increasing post-injury. P65 was confirmed as a critical regulator of the inflammatory response, contributing to neuronal protection and the restoration of neurological function.
    Keywords:  Middle cerebral artery occlusion; Single cell; Stroke; Transcription factor
    DOI:  https://doi.org/10.1038/s41598-025-00524-2
  29. Sci Rep. 2025 May 17. 15(1): 17143
    Microglial depletion prevents visual deficits and retinal ganglion cell loss induced by early life stress in adult animals.
    Juan S Calanni, Laura A Pasquini, Hernán H Dieguez, Nathaly Bernal Aguirre, Bruno G Berardino, Damian Dorfman, Ruth E Rosenstein.
      Early life stress (ELS), a prenatal/early postnatal period of severe trauma, social deprivation, or neglect, among other adversities, constitutes a risk factor for developing psychopathologies and different health complications in adulthood. Maternal separation with early weaning (MSEW) induces long-term consequences in mouse retinal function and structure. We analyzed microglia involvement in adult retina ELS-induced sequelae. C57Bl/6 J mice were separated from the dams at postnatal days (PND) 4-6, 7-9, 10-12, and 13-16, for 2 h, 3 h, 4 h, and 6 h, respectively, and were weaned at PND 17. Control pups were left undisturbed and weaned at PND 21. At PND 45, MSEW induced microgliosis and decreased retinal ganglion cell (RGC) function, followed by RGC loss at PND 60. Microglial phenotypic alterations correlated with a pro-inflammatory profile (i.e., increase in the nuclear levels of nuclear factor kappa B -subunit p65, and C3-, nitric oxide synthase-2, and interleukin-1β-immunoreactivity in Iba-1 ( +) cells). Depleting microglia between PND 35 and 60 did not affect the retina from naïve mice. However, in early stressed mice, it preserved RGC function and number, visually mediated behavior, and contrast sensitivity. Therefore, microglial reactivity could be one of the key factors linking progressive alterations provoked by ELS in adult mice retinal function and structure.
    Keywords:  Early life stress; Microglia; Microglia depletion; Retina; Retinal ganglion cells; Visual functions
    DOI:  https://doi.org/10.1038/s41598-025-01526-w
  30. Sci Rep. 2025 May 19. 15(1): 17355
    Prostaglandin endoperoxide synthase 2 regulates neuroinflammation to mediate postoperative cognitive dysfunction in mice.
    Xuelian Li, Xuemei Li, Qixin Zhang, Yiyun Li, Yingshun Zhou, Jun Zhou, Xiaoxia Duan.
      Prostaglandin endoperoxide synthase 2 (PTGS2) is a rate-limiting enzyme of prostaglandin (PGs) production, mediating perioperative inflammatory response. This study aimed to explore the mechanisms underlying the involvement of PTGS2 in postoperative cognitive dysfunction (POCD). Transient bilateral common carotid artery occlusion (tBCCAO) was performed to induce POCD. The Morris water maze test was used to assess the cognitive function. PTGS2 expression in the hippocampus and plasma was measured. Hippocampal RNA sequencing was performed to determine the pathological basis of POCD. In vivo, the mice were treated with or without a selective PTGS2 inhibitor during the perioperative period. The hippocampi were isolated to detect inflammation and oxidative damage. In vitro, PTGS2 was silenced in BV2 microglial cell lines, and oxygen-glucose deprivation/reoxidation (OGD/R) was performed. Conditioned medium from BV2 cells was collected to culture HT22 hippocampal neurons. Proinflammatory factors and oxidative damage were detected in BV2 and HT22 cells, respectively. The results indicated that the expression of PTGS2 in the plasma and hippocampal tissue of POCD mice was increased and that hippocampal inflammation is an important biological process in POCD. Inhibition of PTGS2 alleviated hippocampal inflammation, and the Morris water maze test showed improved learning and memory functions that were previously impaired. In addition, the inhibition of PTGS2 prevents OGD/R-induced microglial activation and alleviates neuronal injury. In conclusion, PTGS2 may be a culprit in POCD.
    Keywords:  Microglia; Neuroinflammation; Oxidative damage; Postoperative cognitive dysfunction; Prostaglandin endoperoxide synthase 2
    DOI:  https://doi.org/10.1038/s41598-025-01121-z
  31. Sci Rep. 2025 May 23. 15(1): 17955
    M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signaling.
    Jian Li, Qing Chen, Hao Gu.
      Neuronal ferroptosis plays a vital role in the progression of neonatal hypoxic-ischemic brain damage (HIBD). M2-type microglia-derived exosomes (M2-exos) have been shown to protect neurons from ischemia-reperfusion (I/R) brain injury, but their impact on I/R-induced neuronal ferroptosis and the underlying mechanisms remain poorly understood. In this study, we used an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model in HT-22 neuronal cells to investigate how M2-exos modulate ferroptosis. We found that M2-exos were internalized by HT-22 cells and significantly attenuated OGD/R-induced ferroptosis. Mechanistically, M2-exos enhanced mitophagy, which was mediated by the upregulation of FUN14 domain-containing protein 1 (FUNDC1), thereby inhibiting ferroptosis. Further analysis revealed that M2-exos activated FUNDC1-dependent mitophagy through the AMP-activated protein kinase (AMPK)/UNC-51-like kinase 1 (ULK1) signaling pathway. Taken together, these findings suggest that M2-exos ameliorate I/R-induced neuronal ferroptosis by enhancing FUNDC1-mediated mitophagy through the activation of AMPK/ULK1 signaling pathway.
    Keywords:  Exosome; Ferroptosis; Ischemia/reperfusion; Microglia; Mitophagy
    DOI:  https://doi.org/10.1038/s41598-025-03091-8
  32. Front Neurosci. 2025 ;19 1525017
    TREM2 supports neuronal protection and microglial reactivity without an effect on misfolded protein deposition in chronic neurodegenerative prion disease.
    Sarah M Carpanini, Barry M Bradford, Alessio Alfieri, Pedro Piccardo, Jimena Monzón-Sandoval, Deborah Brown, Aileen Boyle, Aleksandra Pokrovskaya, Neil A Mabbott, Jean Manson, Barry W McColl.
       Introduction: Triggering receptor expressed on myeloid cells-2 (TREM2) variants have been identified as risk factors for neurodegenerative disease, including Alzheimer's disease. TREM2 is a cell surface receptor on microglia that regulates homeostatic and immunomodulatory functions, including phagocytosis of apoptotic debris and the resolution of damage-associated inflammation. It remains unclear how TREM2 may mediate an influence on neurodegenerative disease, particularly in relation to key neuropathological hallmarks such as neuronal loss and proteinopathy.
    Methods: We used the ME7 prion disease model to assess the role of TREM2 in the progression and pathology of neurodegenerative disease. Prion diseases are characterised by the accumulation of misfolded prion proteins and provide a highly tractable platform to determine if TREM2 has disease-modifying effects.
    Results: Trem2-/- and wild-type (WT) mice were inoculated intracerebrally with mouse-passaged ME7 scrapie prions, and their effects on CNS disease pathogenesis were determined. Although the accumulation of prion disease-specific PrP was similar in the brains of mice from each group, the severity of neuropathology was increased in Trem2 -/- mice. Morphometric analysis of the microglia also indicated blunted disease-induced reactivity in the brains of infected Trem2-/- mice compared to wild-type (WT) controls. Expression of genes involved in myelination was reduced in prion-infected Trem2-/- mice compared to infected WT mice.
    Conclusion: We conclude that during brain infection with prions, TREM2 supports microglial reactive changes associated with resilience to neuronal loss independently of affecting misfolded PrP deposition. These data imply that TREM2 status may be an important influence on the downstream response to CNS proteinopathy, which alters the susceptibility of neurons and brain tissue to proteinopathy-induced degenerative changes.
    Keywords:  TREM2; microglial reactivity; neurodegenerative disease; neuroinflammation; pathology; prion disease
    DOI:  https://doi.org/10.3389/fnins.2025.1525017
  33. Front Neurosci. 2025 ;19 1575453
    The roles of microglia and astrocytes in neuroinflammation of Alzheimer's disease.
    Jialin Han, Zhi Zhang, Pengfei Zhang, Qian Yu, Qian Cheng, Zhiming Lu, Shuai Zong.
      Alzheimer's disease (AD) is a typical neurodegenerative disease, with the most highlighted pathologic changes identified in the β-amyloid peptide (Aβ) and neurofibrillary tangles (NFTs). Aβ cascade hypothesis, which has seemed to convincingly elucidate the AD pathogenic mechanism, is becoming increasingly disproved, indicating that it is no longer able to explain the emergence of AD entirely. Neuroinflammation offers an alternative explanation for the development of AD. This paper presents an overview of the influence of microglia and astrocytes on neuroinflammation of AD. We further examine the interplay between microglia and astrocyte and their roles as inflammatory mediators. It is hypothesized that targeting these molecular mechanisms associated with neuroinflammation and controlling risk factors may provide a viable therapeutic approach for AD.
    Keywords:  Alzheimer’s disease; NLRP3 inflammasome; astrocyte; microglia; neuroinflammation
    DOI:  https://doi.org/10.3389/fnins.2025.1575453
  34. J Inflamm Res. 2025 ;18 6229-6243
    Integrative Analysis and Experimental Validation Reveal FCGR1A and ITGAL as Key Inflammatory Biomarkers in Proliferative Diabetic Retinopathy.
    Han Yu, Lvyin Luo, Rui Zhang, Fabao Xu, Xueying Yang, Yuhan Wu, Dechang Han, Xuanzhe Chu, Jianqiao Li.
       Purpose: Diabetic retinopathy (DR), one of the most common severe complications of diabetes, has become a leading cause of blindness among the working population without a fundamental treatment. Proliferative DR (PDR) is the advanced stage of DR. Recent studies have shown that inflammation is closely related to PDR, as it promotes leukocyte adhesion, breakdown of the blood-retinal barrier, and pathological neovascularization, but the key regulatory genes involved remained unclear. We aim to identify inflammation-related biomarkers in PDR.
    Methods: We downloaded and merged PDR-related datasets GSE102485, GSE94019, and GSE60436, comprising a total of 13 control samples and 37 samples from PDR patients, and conducted a joint analysis of inflammation-related genes (IRGs). Differential analysis, functional enrichment analysis, WGCNA and LASSO were used to identify key genes and their functions in the pathogenesis of PDR. Dataset GSE241239, which contains retinal sequencing data from mice, was used for external validation. Additionally, single-cell RNA analysis using GSE165784, which includes five human-derived PDR samples, was conducted to investigate the cellular expression of Fc Gamma Receptor IA (FCGR1A) and Integrin Subunit Alpha L (ITGAL). Finally, the expression of FCGR1A and ITGAL was validated in DR mouse models and high glucose-induced cell models.
    Results: Nine key genes associated with the pathogenesis of PDR were identified. Further screening identified FCGR1A and ITGAL as potential therapeutic targets, with single-cell analysis showing their primary distribution in microglia. In vivo and in vitro experiments confirmed localization of FCGR1A and ITGAL in microglia and significant elevation within DR mouse models.
    Conclusion: Comprehensive analysis indicates, for the first time, that FCGR1A and ITGAL are key inflammation-related genes involved in the pathogenesis of PDR mediated by microglia. FCGR1A and ITGAL are promising therapeutic targets for PDR.
    Keywords:  DR mouse model; bioinformatics analysis; inflammatory; microglia; proliferative diabetic retinopathy
    DOI:  https://doi.org/10.2147/JIR.S519725
  35. Neurochem Int. 2025 May 15. pii: S0197-0186(25)00066-X. [Epub ahead of print]187 105993
    Overexpression of TAFA4 in the dorsal root ganglion ameliorates neuropathic pain in male rats through promoting macrophage M2-Skewing.
    Zhangran Ai, Huili Li, Songchao Xu, Chenghui Cai, Xuejuan Wang, Yun Guan, Ruijuan Guo, Yun Wang.
      Neuro-immune interactions between macrophages and primary sensory neurons have been implicated in nerve injury and associated pain. This study aims to explore the function of the TAFA4 as a crucial neuroimmune regulator in modulating macrophage states within the context of neuropathic pain. To elucidate the role of TAFA4 in dorsal root ganglia (DRG) following a chronic constriction injury (CCI) model in male rats, immunofluorescent staining, western blot, flow cytometry analysis and enzyme-linked immunosorbent assay were performed. Microinjection of self-complementary adeno-associated virus expressing TAFA4 mRNA into the L4 and L5 DRGs was conducted to overexpress TAFA4 in the DRGs. Following peripheral nerve injury, we observed a downregulation of TAFA4 in ipsilateral DRG neurons. Restoring this downregulation effectively alleviated the mechanical and thermal nociceptive hypersensitivity by inhibiting pro-inflammatory mediators while promoting the secretion of anti-inflammatory cytokines on day 14 post-CCI. Notably, scAAV-TAFA4 microinjection also facilitated the polarization of macrophages in the DRGs towards the M2 phenotype. Mechanistically, TAFA4 modulates the functions of macrophages in a lipoprotein receptor-related protein 1-dependent manner. Our findings revealed the role of TAFA4 in shifting macrophages in favor of an anti-inflammatory phenotype and enhancing interleukin 10 concentrations in the DRG, suggesting it is a potential analgesic target for alleviating neuropathic pain.
    Keywords:  Cytokine; Dorsal root ganglia; Macrophage; Neuropathic pain; TAFA4
    DOI:  https://doi.org/10.1016/j.neuint.2025.105993
  36. Mol Neurobiol. 2025 May 17.
    High-Fat Diet-Induced Excessive Accumulation of Cerebral Cholesterol Esters and Microglial Dysfunction Exacerbate Alzheimer's Disease Pathology in APPNL-G-F mice.
    Shuhan Yang, Hirofumi Miyazaki, Tunyanat Wannakul, Eiko Amo, Takaomi Saido, Takashi Saito, Hiroki Sasaguri, Motoko Maekawa, Yuji Owada.
      Epidemiological studies have identified high-fat diet (HFD)-induced obesity as a risk factor for Alzheimer's disease (AD), yet the underlying molecular mechanisms remain inadequately elucidated. Microglia, the brain's innate immune cells, are pivotal in AD brain by engulfing β-amyloid (Aβ) peptides and compacting poorly consolidated Aβ plaques. Microglia are highly susceptible to the metabolic milieu; however, it is unclear how long-term HFD alters the lipid environment and influences microglial phenotype in AD brains. In this study, APPNL-G-F knock-in AD model mice were fed an HFD for 9-27 weeks and subsequently analyzed for Aβ pathology and microglial function. Our findings indicated that HFD intake accelerated Aβ deposition, attenuated the recruitment of microglia to the plaques and impaired their phagocytic activity, while also promoting the accumulation of intracellular lipid droplets (LDs). Lipidomic analyses revealed that HFD, in synergy with AD pathology, increased the proportion of cholesterol esters in the cerebral cortex. In vitro, oleic acid-a major HFD constituent-similarly diminished the phagocytic capacity of MG6 microglia and induced LDs accumulation, along with downregulation of gene sets of cholesterol efflux, phagocytosis and engulfment. Overall, these findings implied that HFD-induced perturbation in brain cholesterol homeostasis may compromise microglial activation and expedite AD progression in APPNL-G-F mice.
    Keywords:  Alzheimer’s disease; High-fat diet; Lipid droplet; Lipid metabolism; Microglial function
    DOI:  https://doi.org/10.1007/s12035-025-05052-8
  37. ASN Neuro. 2025 ;17(1): 2506406
    Proliferating Microglia Exhibit Unique Transcriptional and Functional Alterations in Alzheimer's Disease.
    Nàdia Villacampa, Heela Sarlus, Paula Martorell, Khushbu Bhalla, Sergio Gomez-Castro, Ana Vieira-Saecker, Ilya Slutzkin, Kristian Händler, Carmen Venegas, Róisín McManus, Thomas Ulas, Marc Beyer, Eran Segal, Michael T Heneka.
      Proliferation of microglia represents a physiological process, which is accelerated in several neurodegenerative disorders including Alzheimer disease (AD). The effect of such neurodegeneration-associated microglial proliferation on function and disease progression remains unclear. Here, we show that proliferation results in profound alterations of cellular function by providing evidence that newly proliferated microglia show impaired beta-amyloid clearance in vivo. Through sorting of proliferating microglia of APP/PS1 mice and subsequent transcriptome analysis, we define unique proliferation-associated transcriptomic signatures that change with age and beta-amyloid accumulation and are characterized by enrichment of immune system-related pathways. Of note, we identify the DEAD-Box Helicase 3 X-Linked (DDX3X) as a key molecule to modulate microglia activation and cytokine secretion and it is expressed in the AD brain. Together, these results argue for a novel concept by which phenotypic and functional microglial changes occur longitudinally as a response to accelerated proliferation in a neurodegenerative environment.
    Keywords:  Alzheimer’s disease; inflammasome; microglia; proliferation; transcriptome
    DOI:  https://doi.org/10.1080/17590914.2025.2506406
  38. Pharmacol Res. 2025 May 19. pii: S1043-6618(25)00211-7. [Epub ahead of print] 107786
    The regulation of microglia by aging and autophagy in multiple sclerosis.
    Xiying Wang, Ye Sun, Haojun Yu, Chunran Xue, Xuzhong Pei, Yi Chen, Yangtai Guan.
      Multiple sclerosis (MS) is an inflammatory disease that is often characterized by the development of irreversible clinical disability. Age is a strong risk factor that is strongly associated with the clinical course and progression of MS. Several lines of evidence suggest that with aging, microglia have an aging-related gene expression signature and are close to disease-associated microglia (DAM), which exhibit decreased phagocytosis but increased production of inflammatory factors. The gene expression signatures of microglia in MS overlap with those in aging, inflammation and DAM. Moreover, the clearance of damaged myelin by microglia is impaired in the aged brain. Autophagy is a cellular process that decreases in activity with age. In this review, we provide an overview of the role of autophagy and aging in MS. We describe the impact of autophagy and aging on microglial activation in MS and the molecules involved in autophagy and aging, which are related to the phagocytosis and activation of microglia. We propose that a decrease in autophagy in microglia occurs with aging, leading to a decrease in phagocytosis. Decreases in phagocytosis and increases in the production of inflammatory factors by microglia contribute to chronic inflammation in the aged brain and disease progression in MS. Thus, the modulation of autophagy in microglia serves as a potential therapeutic target for MS.
    Keywords:  aging; autophagic targets in multiple sclerosis; autophagy; microglia; multiple sclerosis
    DOI:  https://doi.org/10.1016/j.phrs.2025.107786
  39. Cell Biol Toxicol. 2025 May 23. 41(1): 89
    IFI204 in microglia mediates traumatic brain injury-induced mitochondrial dysfunction and pyroptosis via SENP7 interaction.
    Ting Guo, Yongxing Lai, Shuguang Wu, Chunjin Lin, Xinyu Zhou, Peiqiang Lin, Mouwei Zheng, Jianhao Chen, Fan Lin.
       OBJECTIVES: Traumatic brain injury (TBI) is a primary contributor to chronic functional impairment in human populations, initiating complex neuroinflammatory cascades and neurodegeneration. Despite extensive research efforts, the precise pathophysiological pathways remain incompletely characterized. This investigation aims to establish a novel therapeutic strategy that targets critical molecular pathways post-injury, potentially addressing the current limitations in the clinical management of TBI patients.
    METHODS: The single-cell data of cortical tissue from mice with TBI were obtained from public databases (GSE160763), which was utilized to identify alterations in in the composition of disease-associated cells and related molecules as the disease progresses. Functional and pathway enrichment analyses were conducted to elucidate the functional characteristics of microglia and astrocyte subpopulations. Trajectory analysis was employed to investigate cell differentiation characteristics. Subsequently, we examined the expression and function of microglia-specific molecules, such as IFI204, along with their underlying molecular mechanisms using Western blotting, immunofluorescence, co-immunoprecipitation (CO-IP), histopathology, behavioral tests, and molecular docking to assess binding status, as well as molecular dynamics simulations. Finally, we used molecular docking technology to find small molecule compounds that IFI204 can stably bind to.
    RESULTS: We identified nine major cell populations, most of which undergo dynamic changes following TBI. Astrocytes and microglia were the predominant populations in each group, and further cluster analysis revealed that the proportions of interferon (IFN) and axonogenesis-related microglial subtypes increased after TBI. Trajectory inference analysis indicated that the expression of Ifi204 is upregulated in microglia during disease progression. Conditional microglial knockdown of IFI204 significantly improved neurological deficits in mice, and alleviated mitochondrial dysfunction and microglial pyroptosis. Mechanistically, SENP7, identified as a novel molecule, interacts with IFI204 in microglia, catalyzes the deSUMOylation of IFI204, and promotes STING signal activation, ultimately driving microglial pyroptosis and mitochondrial dysfunction.
    CONCLUSIONS: The interaction between IFI204 and SENP7 promotes microglial pyroptosis and related mitochondrial dysfunction. Furthermore, in the case of TBI, we hypothesize that targeting IFI204 might yield therapeutic benefits.
    Keywords:  IFI204; Microglial pyroptosis; Mitochondria; SENP7; Traumatic brain injury
    DOI:  https://doi.org/10.1007/s10565-025-10032-8
  40. Neuromolecular Med. 2025 May 20. 27(1): 40
    Improvement of Parkinson's Disease Symptoms by Butylphthalide Through Modulation of Microglial Activation.
    Xue Wang, Huimin Shi, Zibin Wei, Ping Liu, Shujuan Tian, Xueqin Song.
      Microglia-mediated neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Studies have shown that butylphthalide (3-n-butylphthalide or NBP) can play an anti-inflammatory role in other diseases by regulating the activation of microglia. This study investigates the neuroprotective and anti-inflammatory effects of NBP in a mouse model of Parkinson's disease (PD) induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The primary aim was to determine whether NBP can improve symptoms of PD by modulating microglial activation and to explore the underlying mechanisms involved. Motor function (assessed via Open Field and Pole Climbing tests), dopaminergic neuronal loss, and activation of different microglial subtypes were assessed in control, MPTP-treated, and NBP + MPTP-treated mice. A p38 phosphorylation inhibitor + MPTP group was also established to investigate potential mechanisms of NBP action. Mice treated with NBP exhibited significantly improved motor function and reduced dopaminergic neuronal loss compared to MPTP-treated mice. In PD mice, pro-inflammatory factor expression was elevated, anti-inflammatory factor expression was reduced, and the expression of arginase-1 (arg-1), a marker for M2 microglia, was decreased. NBP treatment resulted in reduced levels of pro-inflammatory factors, increased levels of anti-inflammatory factors, and elevated arg-1 expression. Additionally, inhibition of p38 phosphorylation further decreased pro-inflammatory factor expression while increasing both anti-inflammatory factor levels and arg-1 expression. The findings indicate that NBP regulates neuroinflammation and improves symptoms of PD by promoting the transformation of microglia to the M2 phenotype, likely mediated through the p38 phosphorylation pathway.
    Keywords:  Butylphthalide; Dopaminergic neuronal loss; Microglial activation; Neuroinflammation; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12017-025-08865-x
  41. Development. 2025 May 19. pii: dev.204610. [Epub ahead of print]
    CSF-1R ligands promote microglial proliferation but are not the sole regulators of developmental microglial proliferation.
    Brady P Hammond, Sameera Zia, Eugene Hahn, Margarita Kapustina, Tristan Lange, Sarah Friesen, Rupali Manek, Kelly V Lee, Adrian Castellanos-Molina, Floriane Bretheau, Mark S Cembrowski, Bradley J Kerr, Steve Lacroix, Jason R Plemel.
      Microglia-the predominant immune cells of the brain and spinal cord-perform essential functions for the development and maintenance of the central nervous system contingent upon the regulated developmental proliferation of microglia. However, the factor(s) that regulate microglial proliferation remain unclear. Here, we confirmed the timeline of developmental proliferation and used bioinformatics to identify potential signalling onto microglia from datasets collected at an age of high developmental microglial proliferation. Of the predicted factors, we found that colony stimulating factor-1 receptor (CSF-1R) ligands boosted proliferation in vitro and were increasingly expressed in the brain across development with each displaying a distinct regional and temporal expression pattern. However, we did not observe a coincident alteration to CSF-1R ligand levels in a model of abnormal developmental proliferation. Together, although CSF-1R ligands can promote microglial proliferation in culture, their developmental expression patterns suggest that they function alongside other unknown factors to regulate developmental microglial proliferation.
    Keywords:  Brain; CSF-1; CSF-1R; Development; IL-34; Microglia; Proliferation
    DOI:  https://doi.org/10.1242/dev.204610
  42. J Neuroimmunol. 2025 May 12. pii: S0165-5728(25)00117-1. [Epub ahead of print]405 578636
    Knockdown of YTHDF2 mitigates OGD-induced microglial inflammation by preventing m6A-dependent PARP14 degradation.
    Bin Li, Ruixi Ming.
      Neuroinflammation is a key pathological factor in ischemic brain diseases, contributing to the initiation and progression of these conditions. The function of the m6A reader protein YTHDF2 in regulating neuroinflammation across various neurological contexts. To elucidate the role and regulatory mechanism of YTHDF2 in inflammation under ischemic-like conditions, this study employed an in vitro model, exposing microglia to oxygen-glucose deprivation (OGD) to mimic the stress environment. And through YTHDF2 knockdown, we investigated its effect on OGD-induced inflammation. The results demonstrated that YTHDF2 knockdown significantly suppressed the expression of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), in OGD-treated microglia. Mechanistic analysis revealed that YTHDF2 interacts with Parp14 mRNA under OGD conditions, reducing its RNA stability via m6A-dependent mechanisms, which in turn decreases Poly (ADP-ribose) polymerase family, member 14 (PARP14) protein expression. Additionally, YTHDF2 knockdown after OGD promoted a PARP14-driven phenotypic switch in microglia from the pro-inflammatory M1 state to the anti-inflammatory M2 state, resulting in diminished inflammation. These findings offer new insights into the regulatory function of YTHDF2 in OGD-induced microglial inflammation and propose m6A modification as a potential therapeutic target for alleviating neuroinflammation.
    Keywords:  M1/M2; Microglia; Neuroinflammation; YTHDF2; m(6)A
    DOI:  https://doi.org/10.1016/j.jneuroim.2025.578636
  43. Gene. 2025 May 15. pii: S0378-1119(25)00360-9. [Epub ahead of print] 149572
    Inhibition of Dectin-1 alleviates inflammation in early diabetic retinopathy by regulating microglia phenotype.
    Wei Sang, Xue Zhang, Qiang Hu, Bo Jiang, Jitian Guan, Zhangxin Huang, Lijun Sun, Dawei Sun.
       BACKGROUND: Diabetic retinopathy (DR) is a major factor in vision loss in diabetic patients, triggering a series of pathological changes. At present, the treatment methods for diabetic retinopathy are limited. There is an urgent need to further explore its mechanism to bring more treatment options to patients.There is increasing evidence that microglia activation plays a crucial role in inflammatory DR. The C type lectin receptor Dectin-1 is known to play an important role in the inflammatory regulation of microglia, however, its role and mechanism in DR remains unclear. This study aims to elucidate the possible mechanisms through which Dectin-1 influences the inflammatory response in high glucose(HG) stimulated microglia and its impact on retinal inflammation during the early stages of DR.
    METHODS: Human microglial cells (HMC3) were stimulated with HG (25 mmol/L), and a streptozotocin (STZ)induced C57BL/6J mouse model was established to simulate DR. To investigate the role of Dectin-1 in HMC3 cells and its underlying molecular mechanisms, we employed western blotting, quantitative realtime PCR (qRT-PCR), hematoxylineosin (H&E) staining, and immunofluorescence analysis.
    RESULTS: Our findings revealed that Dectin-1 levels were elevated in microglia stimulated by HG, playing a pivotal role in cell polarization and the induction of inflammatory factors in vitro. In vivo experiments conducted on STZ induced diabetic mice demonstrated an increased expression of Dectin-1 in retinal tissues. This elevation further promoted the expression of pro inflammatory factors, such as TNF-α, IL-1β, and iNOS, triggering an inflammatory response and causing damage to the retina. Notably, inhibiting Dectin-1 reversed these detrimental effects, ultimately contributing to the delay in the progression of DR. Our investigation also uncovered a significant interaction between Dectin-1 and the downstream pro-inflammatory pathway NF-κB. This interaction occurred through the activation of spleen tyrosine kinase (Syk), both in vitro and in vivo.
    CONCLUSIONS: In summary, our research strongly suggests that Dectin-1 plays a crucial pro-inflammatory role in early DR. This mechanismis, at least in part, mediated through the Syk/NF-κB pathway. Consequently, inhibition of Dectin-1 is expected to become a potential therapeutic target for delaying DR.
    Keywords:  Dectin-1; Diabetic retinopathy; Inflammation; Microglia polarization; NF-κB signaling pathway
    DOI:  https://doi.org/10.1016/j.gene.2025.149572
  44. Cell Mol Neurobiol. 2025 May 19. 45(1): 45
    The Hallmarks of Ageing in Microglia.
    Laura Carr, Sanam Mustafa, Lyndsey E Collins-Praino.
      As ageing is linked to the development of neurodegenerative diseases (NDs), such as Alzheimer's Disease and Parkinson's Disease, it is important to disentangle the independent effect of age-related changes from those due to disease processes. To do so, changes to central nervous system (CNS) cells as a function of advanced age need better characterisation. Microglia are of particular interest due to their proposed links with the development and progression of NDs through control of the CNS immune response. Therefore, understanding the extent to which microglial dysfunction is related to phyisological ageing, rather than a disease process, is critical. As microglia age, they are believed to take on a pro-inflammatory phenotype with a distinct dystrophic morphology. Nevertheless, while established hallmarks of ageing have been investigated across a range of other cell types, such as macrophages, a detailed consideration of functional changes that occur in aged microglia remains elusive. Here, we describe the dynamic phenotypes of microglia and evaluate the current state of understanding of microglial ageing, focusing on the recently updated twelve hallmarks of ageing. Understanding how these hallmarks present in microglia represents a step towards better characterisation of microglial ageing, which is essential in the development of more representative models of NDs.
    Keywords:  Ageing; Immunosenescence; Inflammageing; Microglia; Morphology; Neuroinflammation
    DOI:  https://doi.org/10.1007/s10571-025-01564-y
  45. Cell Immunol. 2025 Apr 22. pii: S0008-8749(25)00043-7. [Epub ahead of print]413 104958
    Apelin-13 enhances neurofunctional recovery and suppresses neuroinflammation via the SIRT1/NF-κB axis in ischemic stroke.
    Zhe Peng, Dewen Ru, Guangpeng Leng, Jinghua Peng, Meng Zhang, Bin Cai.
       BACKGROUND: Ischemic stroke is a major cause of mortality and disability, with neuroinflammation driving secondary brain injury. Microglial activation contributes to neuronal apoptosis, BBB disruption, and prolonged neurological deficits. Apelin-13, an endogenous peptide, has demonstrated neuroprotective potential, but its precise mechanisms remain unclear. This study investigates how Apelin-13 modulates neuroinflammation and the molecular pathways involved in ischemic stroke.
    METHODS: Mice underwent middle cerebral artery occlusion-reperfusion (MCAO/R) to model ischemic stroke, followed by Apelin-13 administration. Neurological function was assessed using Garcia scoring, adhesive removal, rotarod, and grid-walking tests. Infarct volume was quantified via TTC staining, and MRI evaluated cerebral edema. Immunofluorescence staining and Western blotting were used to assess neuronal apoptosis and BBB integrity. Microglial activation and polarization were analyzed via Iba1 co-immunostaining with CD16 (pro-inflammatory) and Arg1 (anti-inflammatory) markers. In vitro, primary microglia and BV2 cells were exposed to oxygen-glucose deprivation (OGD) to mimic ischemia, and Apelin-13's effects on inflammatory signaling were examined. The role of the SIRT1/NF-κB axis was evaluated using the SIRT1 inhibitor EX-527.
    RESULTS: Apelin-13 significantly improved post-stroke neurological function, reduced infarct volume, and alleviated cerebral edema. It preserved BBB integrity by reducing vascular leakage and albumin extravasation and suppressed neuronal apoptosis by downregulating cleaved caspase-3. Apelin-13 also mitigated neuroinflammation by decreasing microglial activation and shifting polarization toward an anti-inflammatory phenotype, as evidenced by reduced CD16+ and increased Arg1+ microglia. In vitro, Apelin-13 suppressed OGD-induced pro-inflammatory cytokine release while promoting anti-inflammatory responses. Mechanistically, Apelin-13 upregulated SIRT1, inhibiting NF-κB signaling and reducing inflammatory mediator expression. SIRT1 inhibition with EX-527 reversed these effects, restoring NF-κB activation and pro-inflammatory microglial polarization.
    CONCLUSIONS: Apelin-13 exerts neuroprotective effects in ischemic stroke by preserving BBB integrity, reducing neuronal apoptosis, and suppressing neuroinflammation. These effects are mediated through SIRT1 activation and NF-κB inhibition. Targeting the Apelin-13/SIRT1/NF-κB axis may offer a promising therapeutic strategy for mitigating neuroinflammation and improving stroke recovery.
    Keywords:  Apelin-13; Ischemic stroke; NF-κB signaling; Neuroinflammation; SIRT1
    DOI:  https://doi.org/10.1016/j.cellimm.2025.104958
  46. Hum Cell. 2025 May 20. 38(4): 101
    The role of microglia in the development of diabetic retinopathy and its potential clinical application.
    Tingting Lu, Jiameng Shang, Shengdan Pu, Yuxin Xu, Xiaotong Sun, Xinyuan Gao.
      Lately, research on the function of microglia in diabetic retinopathy (DR) is becoming increasingly focused. Microglia are immune cells that dwell in the central nervous system and are crucial to the pathophysiology of DR. According to studies, a hyperglycemic environment can activate microglia, bringing them out of a resting state to an active state. This allows them to release a variety of inflammatory factors and chemokines, which can then cause retinal inflammatory reactions. When it comes to angiogenesis in DR, activated microglia release a variety of angiogenic substances, such as vascular endothelial growth factor (VEGF), to create aberrant new blood vessels. Moreover, microglia contribute to the retina's oxidative stress process by generating and releasing reactive oxygen and nitrogen-free radicals, which exacerbates retinal damage. Researchers have proposed a variety of strategies for the activation of microglia and the inflammatory response it triggers. By inhibiting the excessive activation of microglia and reducing the release of inflammatory factors, the inflammatory response and damage to the retina can be alleviated. Drugs that interfere with retinal microglia can also be used to regulate vascular damage and inhibit the formation of new blood vessels. In addition, antioxidants are used to remove reactive oxygen and free radicals, reduce oxidative stress levels, and protect retinal cells. These therapeutic strategies aim to achieve the purpose of treating DR by regulating the function of microglia. Thus, we highlight the possibility that therapy aimed at microglia could offer fresh ideas for treating DR.
    Keywords:  Anti-inflammatory therapy; Diabetic retinopathy; Inflammation; Microglia; Oxidative stress; Retinal neovascularization
    DOI:  https://doi.org/10.1007/s13577-025-01226-7
  47. Metab Brain Dis. 2025 May 17. 40(5): 207
    Microglial activation as a hallmark of neuroinflammation in Alzheimer's disease.
    Rasoul Ebrahimi, Shahrzad Shahrokhi Nejad, Mahdi Falah Tafti, Zahra Karimi, Seyyedeh Reyhaneh Sadr, Dana Ramadhan Hussein, Niki Talebian, Khadijeh Esmaeilpour.
      Microglial activation has emerged as a hallmark of neuroinflammation in Alzheimer's disease (AD). Central to this process is the formation and accumulation of amyloid beta (Aβ) peptide and neurofibrillary tangles, both of which contribute to synaptic dysfunction and neuronal cell death. Aβ oligomers trigger microglial activation, leading to the release of pro-inflammatory cytokines, which further exacerbates neuroinflammation and neuronal damage. Importantly, the presence of activated microglia surrounding amyloid plaques is correlated with heightened production of cytokines such as interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α), creating a vicious cycle of inflammation. While microglia play a protective role by clearing Aβ plaques during the early stages of AD, their chronic activation can lead to detrimental outcomes, including enhanced tau pathology and neuronal apoptosis. Recent studies have highlighted the dualistic nature of microglial activation, showcasing both inflammatory (M1) and anti-inflammatory (M2) phenotypes that fluctuate based on the surrounding microenvironment. Disruption in microglial function and regulation can lead to neurovascular dysfunction, further contributing to the cognitive decline seen in AD. Moreover, emerging biomarkers and imaging techniques are unveiling the complexity of microglial responses in AD, providing avenues for targeted therapeutics aimed at modulating these cells. Understanding the intricate interplay between microglia, Aβ, and tau pathology is vital for developing potential interventions to mitigate neuroinflammation and its impact on cognitive decline in AD. This review synthesizes current findings regarding microglial activation and its implications for AD pathogenesis, offering insights into future therapeutic strategies.
    Keywords:  Alzheimer’s disease; Microglia; Neuroinflammation; Review
    DOI:  https://doi.org/10.1007/s11011-025-01631-9
  48. Int J Biol Sci. 2025 ;21(7): 3011-3029
    SIRT3 is required for the protective function of ketogenic diet on neural inflammation and neuropathic pain.
    Mengqiu Deng, Yuanyuan Fang, Yan Chu, Ruifeng Ding, Xiaoyi Fan, Huawei Wei, Honghao Song, Guowei Jiang, Hailing Zhang, Chaofeng Han, Hongbin Yuan.
      Chronic neuroinflammation is a key pathological feature of neuropathic pain. The ketogenic diet (KD) has demonstrated potential to reduce neuronal excitability and alleviate inflammation in epilepsy, yet its effects and precise mechanisms in neuropathic pain remain elusive. We first observed that β-hydroxybutyrate (BHB), a key metabolite induced by KD, was reduced in mice following neuropathic pain induced by chronic constriction injury (CCI). Subsequently, we demonstrated that KD effectively alleviated CCI-induced thermal hyperalgesia and mechanical allodynia, while mitigating neuroinflammation through reduced microglial activation and pro-inflammatory cytokine levels. BHB reduced reactive oxygen species (ROS) production, which coincided with enhanced mitochondrial membrane potential in microglia, thereby attenuating microglia-mediated inflammatory responses. Both in vivo and in vitro experiments revealed KD-induced upregulation of uncoupling protein 2 (UCP2), sirtuin 3 (SIRT3) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) in the spinal dorsal horn. Importantly, SIRT3 deficiency abolished KD's protective effects against neuropathic pain and reduced BHB levels, potentially attributable to diminished expression of hepatic ketone body synthases and spinal ketone body-utilizing enzymes. These findings highlight SIRT3 as a promising therapeutic target for neuropathic pain within the ketogenic diet paradigm, providing a foundation for novel therapeutic strategies.
    Keywords:  ketogenic diet; microglia; neuropathic pain; sirtuin 3; β-hydroxybutyrate
    DOI:  https://doi.org/10.7150/ijbs.110921
  49. Phytomedicine. 2025 May 10. pii: S0944-7113(25)00474-X. [Epub ahead of print]143 156836
    Regulation of inflammation by Chaihu-Shugan-San: Targeting the IL-17/ NF-κB pathway to combat breast cancer-related depression.
    Zhongyuan Qu, Huimin Li, Fajing Qiang, Kaili Liu, Shuang Wu, Jianli Li, Xiang Zou.
       BACKGROUND: Breast cancer-related depression (BCRD) is one of the severest comorbidities, affecting the quality of life and the treatment efficacy in BC patients. Chaihu-Shugan-San (CSS), a traditional Chinese medicine presents a potential therapeutic method in BCRD.
    PURPOSE: The main purpose of the research was to investigate the effects of CSS on BCRD in a mouse model and to elucidate its mechanisms, particularly its impact on microglial polarization through the IL-17/ NF-κB pathway.
    METHODS: A mouse BCRD model was constructed and treated with CSS. Behavioral testing, biochemical parameters, H&E staining, and small animal imaging were used to assess the depressive-like behaviors and tumor growth in mice. RNA sequencing analysis was performed, and the data were authenticated by Western blot as well as quantitative qRT-PCR to explore the mechanisms of CSS treatment in BCRD. The BV2 microglia were stimulated with LPS in vitro and intervened by IL-17 protein, IL-17 antagonist, IMD-0354, and CSS. In addition, western blot was utilized to confirm the expression of IL-17/ NF-κB pathway-related factors. Molecular docking technique and UPLC-Q-TOF/MS were used to find out the key active components of CSS.
    RESULTS: CSS treatment significantly improved depression-like behaviors and retarded tumor growth in mice. Through RNA sequencing analysis, it was indicated that the improvement of BCRD by CSS was highly associated with the regulation of the IL-17/ NF-κB pathway. Western blot and qRT-PCR outcomes suggested that CSS inhibited the IL-17/ NF-κB pathway, facilitating the transformation from pro-inflammatory M1 microglial phenotype to anti-inflammatory M2 phenotype, contributing to the reduction of neuroinflammation. In vitro experiments demonstrated that CSS modulated the immune reaction through the induction of phenotypic transformation of microglia from M1 toward M2 phenotype, hence reducing neuroinflammation. Notably, this therapeutic effect of CSS was highly similar to the effects of IL-17 antagonists, thus suggesting that CSS alleviates the symptoms of BCRD by targeting IL-17. Molecular docking revealed that the major bioactive compounds in CSS were Saikosaponin A, Saikosaponin C, and Saikosaponin D.
    CONCLUSION: This study systematically demonstrates that CSS ameliorates BCRD by suppressing the IL-17/ NF-κB pathway as well as modulating microglial polarization and elucidates the dual function of IL-17. These results point to a new multi-target intervention strategy for BCRD treatment and fully reflect the holistic effects of CSS by its multi-component as well as multi-target actions.
    Keywords:  Breast cancer; Chaihu-Shugan-San; Depression; IL-17/ NF-κB pathway; Microglia
    DOI:  https://doi.org/10.1016/j.phymed.2025.156836
  50. Exp Brain Res. 2025 May 16. 243(6): 149
    Soluble TREM2 ameliorates pathological phenotypes in ischemic stroke models via modulating neuronal and microglial functions.
    Yanfei Guan, Feng Gao, Bo Chen, Tiansheng Yu, Linxin Meng, Qingzhuang Chen, Xiaodan Xiao.
      Although the neuroprotective effects of triggering receptor expressed on myeloid cell 2 (TREM2) upregulation after ischemic stroke has been demonstrated, the level change and effect of soluble TREM2 (sTREM2) derived from proteolytic cleavage of the TREM2 extracellular domain in ischemic stroke remain unknown. In our study, the level and function of sTREM2 were detected in neuron-microglia co-cultures subjected to oxygen glucose deprivation (OGD) and in the ischemic striatum of C57BL/6 J mice in a transient middle cerebral artery occlusion (tMCAO) model. sTREM2's effect on neuronal nitric oxide synthase (nNOS)-postsynaptic density protein-95 (PSD-95) interaction was determined by co-immunoprecipitation. The microglial-activated morphology in the striatum was identified by immunohistochemistry. Quantitative real-time polymerase chain reactionwas used to detect the transcriptional levels of TREM2, shorter variant TREM2, insulin-like growth factor 1, interleukin (IL)-4, and IL-13. Levels of sTREM2, generated through the cleavage of full-length TREM2 at the His157-Ser158 peptide bond, declined after OGD and tMCAO. sTREM2 reduced neuronal death after OGD and alleviated brain infarction and neurological deficits after tMCAO by disrupting the nNOS-PSD-95 interaction, promoting microglial activation, and increasing the expression of some cytokines associated with microglial polarization towards an anti-inflammatory phenotype. To the best of our knowledge, this is the first study to suggest that sTREM2 protects against transient cerebral ischemia.
    Keywords:  Interaction; Ischemic stroke; Microglia; Neuron; Soluble TREM2; Striatum
    DOI:  https://doi.org/10.1007/s00221-025-07094-9
  51. Alzheimers Res Ther. 2025 May 22. 17(1): 114
    Novel fully human high-affinity anti-TREM2 antibody shows efficacy in clinically relevant Alzheimer´s mouse model.
    Markus Kraller, Julia Faßbender, Ammar Jabali, Joseph Kroeger, Barbara Fink, Bastian Popper, Martin Ungerer, Miriam A Christlmeier.
       BACKGROUND: New drugs to treat Alzheimer´s disease (AD) are urgently needed. Human triggering receptor expressed on myeloid cells 2 (hTREM2) is a validated drug target which is genetically associated with AD. Existing anti-hTREM2 antibodies were raised in animal immune systems, and subsequently humanized, which may incur immunological complications upon repeated preventive or therapeutic applications in vivo in AD patients. In addition, anti-hTREM2 antibodies should be optimized for both, efficacy and safety.
    METHODS: A novel fully human monoclonal brain-targeting anti-hTREM2 antibody M07-TFN was created. Binding affinities, cell viabilities, and agonist potencies were investigated on rhTREM2 and in human microglia. Transcytosis assays modeled blood-brain barrier translocation (BBB). Behavior tests were carried out in 5 × familiar AD (5xFAD) mice of both genders, to test for brain function and cognition as well as hippocampus-dependent spatial memory using the Barnes maze. In addition, amyloid plaque formation was determined on brain sections at the end of the study.
    RESULTS: M07-TFN showed higher binding affinities and stronger activation of hTREM2 signaling than all previously described anti-hTREM2 antibodies. p-Syk activation was increased 30-fold in hTREM2-overexpressing HEK293 cells and fourfold in human microglia cells compared to baseline. Human microglia viability significantly improved after stress testing. M07-TFN showed strong BBB translocation in a human BBB model, and exerted cross-reactivity to the mouse TREM2 stalk region, which allowed us to investigate M07-TFN directly in an AD mouse model. In 5xFAD mice, M07-TFN resulted in improved novel object location and better spatial orientation and memory, and significantly reduced plaque load. Additional safety investigations in mice showed no negative effects on blood cells or major organs.
    CONCLUSION: Compared to existing humanized anti-hTREM2 antibodies that have been investigated in clinical trials, M07-TFN showed best-in-class affinities and agonist potencies. Being a fully human anti-hTREM2 antibody, M07-TFN holds the promise of reduced immunogenicity for use in human patients.
    Keywords:  Alzheimer’s disease; Antibody; Microglia; Neurodegeneration; TREM2
    DOI:  https://doi.org/10.1186/s13195-025-01759-x
  52. Harmful Algae. 2025 Jun;pii: S1568-9883(25)00064-2. [Epub ahead of print]146 102862
    Domoic acid induces developmental stage-specific effects on microglia in zebrafish.
    Alia S Hidayat, Jordan A Pitt, Helen Fredricks, Mark E Hahn, Neelakanteswar Aluru.
      Harmful algal blooms (HABs), driven by warming oceans and increased eutrophication, are negatively affecting aquatic ecosystems as well as human health. Blooms of diatom Pseudo-nitzschia spp. produce a neurotoxin, domoic acid (DA), which can be concentrated by filter feeders, including shellfish. Consumption of DA-contaminated seafood causes amnesic shellfish poisoning. DA causes well-established effects on neurons, inducing neurotoxicity by binding to ionotropic glutamate receptors. However, its effects on non-neuronal cells including microglia, the resident immune cells in the brain, are less well understood. Microglia play critical roles in brain health, and disruptions in microglial activity during development can have long-term impacts on brain function and disease risk. The objective of this study was to examine the effects of developmental DA exposure on microglia using zebrafish (Danio rerio). We characterized effects of DA exposure on microglial abundance and morphology at two developmental stages (2 and 4 days post-fertilization (dpf)). We additionally assessed impacts on cell death, cytokine expression, and startle response behavior. In older larvae (4 dpf), microglial effects occurred only at the highest dose (0.3 ng DA per larvae) and coincided with severe morphological defects. In contrast, 2 dpf exposure to lower doses (0.1 ng DA per embryo) caused transient tremors without gross abnormalities but exposure to either 0.1 or 0.3 ng DA per larvae increased microglial abundance and altered microglial morphology. In contrast, 4 dpf exposure to 0.3 ng DA per larvae reduced microglial numbers. Increases in mRNA levels of il1b, il4, and tgfb were observed after 4 dpf exposure, but no significant cytokine changes were detected at 2 dpf. Overall, the effects of DA are highly developmental stage-specific, with microglial reactivity occurring at doses that do not cause gross morphological changes. These findings suggest that neuroinflammation may arise at lower DA doses, indicating a potential mechanism for subtle toxic effects and emphasizing the need for further research to better understand the consequences of low-dose DA exposure on microglial function.
    Keywords:  Amnesic shellfish poisoning; Brain; Glial cells; Glutamate receptor; Harmful algal blooms; Neurotoxicity
    DOI:  https://doi.org/10.1016/j.hal.2025.102862
  53. Neurosci Biobehav Rev. 2025 May 14. pii: S0149-7634(25)00206-4. [Epub ahead of print]174 106206
    A restarted life: Resetting microglia innate immune memory.
    Fangyuan Cheng, Bo Yan, Fanglian Chen, Ping Lei.
      Microglia can achieve depletion and repopulation through various mechanisms, improving outcomes in multiple CNS diseases. Innate immune memory in microglia can undergo continuous reprogramming through epigenetics, facilitating iterative memory upgrades. Here, through a comprehensive literature review, we propose the concepts of the microglial innate immune memory prototype (MIIMP) and microglial temporally phased innate immune memory reset (MTPIIMR). The temporally phased innate immune memory are reflected not only in the formation of immune response prototypes in microglia but also in the partial reset of innate immune memory during the depletion and repopulation process. In the duel against time, single cycles of depletion and repopulation can yield benefits through partial innate immune memory reset, while multiple cycles accelerate microglial aging. Identifying the optimal solution to replace microglia for filling ecological niches and executing their functions perfectly is a formidable yet profoundly significant challenge.
    Keywords:  CSF1R inhibitor; Innate immune memory; Microgia; Repopulation
    DOI:  https://doi.org/10.1016/j.neubiorev.2025.106206
  54. Kaohsiung J Med Sci. 2025 May 20. e70041
    Relaxin-2 Ameliorates Spinal Cord Injury by Inhibiting Microglia Activation.
    Ji-Huan Wang, Hong-Biao Sheng, Jun-Kun Li.
      This study aims to assess the therapeutic effectiveness of Relaxin-2 (RLN-2) in promoting functional recovery and neuroprotection following spinal cord injury (SCI) in mice. Furthermore, continuous subcutaneous infusion of Serelaxin (0.5 mg/kg/day; human recombinant relaxin-2) improved neurological recovery, as evidenced by higher Basso-Beattie-Bresnahan (BBB) scores and reduced foot-stepping angles compared to the SCI group. Additionally, RLN-2 effectively reduced edema in the injured spinal cord, as shown by decreased water content and downregulated AQP4 expression at mRNA and protein levels. RLN-2 reduced oxidative stress markers such as malondialdehyde (MDA) and reactive oxygen species (ROS) and increased the activity of catalase (CAT). Further, RLN-2 mitigated neuroinflammation by reducing the levels of pro-inflammatory cytokines (TNF-α and IL-6) and by inhibiting the activation of M1 microglia while promoting the polarization of M2 microglia. It also inhibited the activation of the NF-κB signaling and strengthened the activation of the STAT6 signaling in the spinal cord of SCI mice. These findings suggest that RLN-2 may be a promising therapeutic agent for the treatment of spinal cord injury.
    Keywords:  AQP4; BBB; M2 microglia activation; Relaxin‐2; spinal cord injury (SCI)
    DOI:  https://doi.org/10.1002/kjm2.70041
  55. Life Sci. 2025 May 21. pii: S0024-3205(25)00388-1. [Epub ahead of print] 123753
    Transcranial direct current stimulation alleviates chronic pain in knee osteoarthritis by modulating microglial and astrocytic polarization and neuroinflammation.
    Rujuan Liu, Ting Zhu, Xiao Chu, Yifan Xu, Lin Wang, Qi Wan, Tieshan Li.
       AIMS: Knee osteoarthritis (KOA) chronic pain is linked to neuroinflammation mediated by reactive astrocytes in the primary somatosensory cortex (S1). Reactive astrocytes are classified into neurotoxic A1 and neuroprotective A2 phenotypes, with activated microglia promoting A1 astrocyte formation during chronic pain progression. This study aimed to investigate whether transcranial direct current stimulation (tDCS) can alleviate KOA chronic pain by modulating glial phenotype conversion and neuroinflammatory processes.
    MAIN METHODS: Rats received an intra-articular injection of monosodium iodoacetate (MIA) in the left knee to model KOA pain. Additionally, rats received intraperitoneal injections of the NF-κB inhibitor BAY 11-7082 and underwent tDCS. Pain thresholds were assessed using von Frey filaments and a hot plate. Changes in microglia, astrocytes, and inflammatory factor expression were analyzed with Western blotting, immunofluorescence, and reverse transcription-quantitative PCR.
    KEY FINDINGS: At 4 and 7 days after MIA injection, microglia exhibited a proinflammatory M1 phenotype, accompanied by increased expression of IL-1α, TNF-α, and C1q. From day 7 to 21 post-injection, astrocytes displayed a neurotoxic A1 phenotype. The NF-κB/NLRP3/IL-18 signaling pathway was significantly upregulated in KOA rats. Treatment with BAY 11-7082 or tDCS significantly alleviated mechanical allodynia and thermal hyperalgesia, shifting microglia from M1 to M2 and astrocytes from A1 to A2 polarization, while suppressing the NF-κB/NLRP3/IL-18 pathway and reducing neuroinflammation.
    SIGNIFICANCE: These findings suggest that tDCS may alleviate KOA chronic pain through modulation of glial activation states and suppression of central neuroinflammation, highlighting its potential as a non-invasive therapeutic approach.
    Keywords:  Astrocytes polarization; Central sensitization; Chronic pain; Knee osteoarthritis; Neuroinflammation; Transcranial direct current stimulation
    DOI:  https://doi.org/10.1016/j.lfs.2025.123753
  56. Invest Ophthalmol Vis Sci. 2025 May 01. 66(5): 31
    Single-Cell RNA Sequencing of the Primary Visual Cortex in Mice With Optic Nerve Injury.
    Deling Li, Bin Zou, Qinyuan Hu, Xinyi Zhang, Weiting Zeng, Liling Liu, Minbin Yu.
       Purpose: Glial cells play a critical role in primary visual cortex (V1 region) damage caused by optic nerve injury, but the mechanisms driving progression of V1 region injury and glial cell heterogeneity remain poorly understood. This study aimed to investigate the damage changes in the V1 region of mice after optic nerve crush (ONC) by single-cell RNA sequencing (scRNA-seq).
    Methods: Hematoxylin and eosin (H&E) and immunofluorescence staining were used to evaluate the changes of retinal thickness, astrocytes, and microglia in the V1 region after ONC in mice. Single cell suspensions in the V1 region of mice were prepared and analyzed by scRNA-seq with Seurat, cellchat, CytoTRACE in R software. The expression of PTGDS and CRYAB was measured by qPCR, Western blot, and immunofluorescence.
    Results: After unilateral ONC, retinal thinning in both eyes and activation of astrocytes and microglia in contralateral V1 region were observed. Genes related to neuroinflammation and apoptosis in the bilateral V1 region were upregulated, and the related pathways included MAPK, TNF, and apoptosis signaling pathways. Notably, the V1 region contralateral to the ONC eye exhibited more pronounced differential gene expression, and the protein expression of neuroinflammation-related genes Ptgds and Cryab increased. We further investigated the heterogeneity and pseudotime trajectories of astrocytes and microglia, demonstrating the key branches that dominate neuroinflammation.
    Conclusions: This study generates an atlas of the V1 region of the mouse brain, highlighting the role of astrocytes and microglia in the damage changes in the V1 region after ONC, and suggesting Ptgds and Cryab as potential targets to reduce neuroinflammation.
    DOI:  https://doi.org/10.1167/iovs.66.5.31
  57. Acta Neuropathol Commun. 2025 May 19. 13(1): 105
    Microglial repopulation reverses radiation-induced cognitive dysfunction by restoring medial prefrontal cortex activity and modulating leukotriene-C4 synthesis.
    Yubo Hu, Zhe Li, Yafeng Zhu, Mengdan Xing, Xiaoru Xie, Panwu Zhao, Xin Cheng, Chuan Xiao, Yuting Xia, Jingru Wu, Yuan Luo, Ho Ko, Yamei Tang, Xiaojing Ye, Wei-Jye Lin.
      Cranial radiotherapy and environmental radiation exposure are associated with increased risk of cognitive dysfunction, including memory deficits and mood disorders, yet the underlying mechanisms remain poorly understood. In this study, we demonstrate that cranial irradiation induces hypoactivity in the medial prefrontal cortex (mPFC) of mice, leading to anxiety-like behaviors and memory impairments, which can be prevented by optogenetic activation of mPFC excitatory neurons. Radiaiton exposure also causes a significant reduction in microglial density within the mPFC, accompanied by morphological and transcriptional alterations in the remaining microglia. Notably, microglial repopulation, achieved through CSF1R antagonist-mediated depletion prior to irradiation and subsequent repopulation, restores mPFC neuronal acitivity and reverses cognitive and behavioral deficits. Integrated bulk RNA sequencing and microglial proteomic analysis of the mPFC reveal that microglial repopulation specifically modulates the leukotriene-C4 biosynthesis pathway, without significant changes in canonical pro-inflammatory cytokines or chemokines. Importantly, pharmacological inhibition of leukotriene-C4 synthase ameliorates radiation-induced anxiety and memory impairments. These findings identify leukotriene-C4 signaling as a critical mechanism underlying radiation-induced cognitive dysfunction and suggest that microglial repopulation and targted inhibition of leukotriene-C4 represent potential therapeutic strategies for mitigating radiation-associated cognitive disorders.
    Keywords:  Leukotriene-C4; Medial prefrontal cortex; Microglia; Neuroinflammation; Radiation-induced brain injury
    DOI:  https://doi.org/10.1186/s40478-025-02026-8
  58. J Ethnopharmacol. 2025 May 20. pii: S0378-8741(25)00696-8. [Epub ahead of print] 120010
    Icariin alleviates cognitive dysfunction by reducing neuroinflammation via the cGAS-STING pathway.
    Fengjuan Lu, Lu Li, Bilian Zheng, Ce Wang, Ziying Liu, Xingshuo Huang, Linyue Song, Chong Ding, Yang Li.
       ETHNOPHARMACOLOGICAL RELEVANCE: Epimedium brevicornu Maxim., a Chinese herbal medicine, is known for its efficacy in nourishing the kidneys. Icariin (ICA), the primary active ingredient in Epimedium brevicornu Maxim., possesses multiple pharmacological properties, yet its impact on Alzheimer's disease (AD) warrants further exploration.
    AIM OF THE STUDY: Study aims to explore the inhibitory impact of ICA on neuroinflammation in AD via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway.
    MATERIALS AND METHODS: SPF-grade male ICR mice were used to establish an AD model by lateral ventricle injection of Aβ1-42. Behavioral, pathological assessments, as well as immunofluorescence staining, molecular docking, and Western blot analyses, were conducted to evaluate the effects of ICA treatment on memory function, neuronal damage, neuroinflammation, and the cGAS- STING pathway in mice.
    RESULTS: ICA significantly improved memory impairment, alleviated neuronal damage and apoptosis, and suppressed neuroinflammation in AD mice. Additionally, ICA inhibited microglial hyperactivation, promoting the transition from the M1 to the M2 phenotype. It specifically inhibited the activation of the cGAS-STING pathway and down-regulated the expression of cGAS, STING, p-TBK1/TBK1, p-IRF3/IRF3 and p-NF-κB/NF-κB. Furthermore, molecular docking revealed that the binding energy between ICA and cGAS was -7.07 kcal/mol, indicating a stable interaction. Further validation using the cGAS-selective small molecule inhibitor RU.521 confirmed the protective effects of ICA against cGAS-STING signaling on microglial transformation and neuroinflammation.
    CONCLUSION: ICA exhibits therapeutic potential in AD by inhibiting microglial transformation and neuroinflammation through the cGAS-STING pathway, positioning it as a candidate drug for AD treatment targeting this pathway.
    Keywords:  Alzheimer’s disease; Icariin; Microglia; Neuroinflammation; cGAS-STING pathway
    DOI:  https://doi.org/10.1016/j.jep.2025.120010
  59. Ecotoxicol Environ Saf. 2025 May 21. pii: S0147-6513(25)00700-6. [Epub ahead of print]299 118364
    Characterizing microglial heterogeneity in autophagy impairment of Paraquat-induced Parkinson's disease-like neurodegeneration.
    Yu Zhang, Yihua Jiang, Zhen Yu, Yinhan Li, Zhiyu Zhang, Fuli Zheng, Hong Hu, Guangxia Yu, Zhenkun Guo, Siying Wu, Wenya Shao, Huangyuan Li.
      Parkinson's disease (PD) is a prevalent neurodegenerative condition influenced by environmental elements, notably Paraquat (PQ), which is one of the known risk factors. Impaired autophagy is a critical factor in the pathogenesis of PD, yet the cellular heterogeneity related to autophagy in PD has not been thoroughly investigated. Here, we established a PQ-induced PD-like neurodegeneration model and found that PQ impairs autophagy during experimental PD progression. Using single-cell RNA sequencing (scRNA-seq), we elucidated the autophagy-related transcriptomic landscapes in this model, identifying microglia as the central cell type associated with PQ-induced autophagy across all brain cell types. Additionally, microglial subtypes in the PQ-exposed model exhibited significant heterogeneity in gene expression characteristics, biological functions, and roles in autophagic regulation. PQ exposure induced potential genetic transformations between microglial subtypes, which may further disrupt their immune response and energy metabolism regulation functions. Subsequently, we validated the identity transformation of microglia revealed by scRNA-seq in both in vivo and in vitro PQ exposure models. Moreover, we identified a specific microglial subtype primarily responsible for the autophagy-related changes observed in the PQ-exposed model. The expression of the autophagic subtype marker gene Inpp5d may contribute to the regulation of PQ-induced autophagic impairment in BV2 cells. This study generates the first scRNA-seq atlas of autophagy in the context of PQ exposure, highlighting the heterogeneity of microglial subtypes and identifying an autophagy-specific microglial subtype as a central mechanism in the pathology of PQ-induced PD-like neurodegeneration.
    Keywords:  Autophagy; Cell heterogeneity; Microglia; Paraquat; Parkinson’s disease; Single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118364
  60. Acta Physiol (Oxf). 2025 Jun;241(6): e70060
    Chronic High-Fat Diet Consumption Followed by Lipopolysaccharide Challenge Induces Persistent and Long-Lasting Microglial Priming, Mediates Synaptic Elimination via Complement C1q, and Leads to Behavioral Abnormalities in Male Wistar Rats.
    Titikorn Chunchai, Hiranya Pintana, Chanon Kunasol, Patcharapong Pantiya, Busarin Arunsak, Sasiwan Kerdphoo, Wichwara Nawara, Suriphan Donchada, Nattayaporn Apaijai, Jirapas Sripetchwandee, Chanisa Thonusin, Nipon Chattipakorn, Siriporn C Chattipakorn.
       AIM: Microglia exhibit innate immune memory, altering their responses to subsequent challenges. Consumption of high-fat diet (HFD) triggers innate immune responses, but the characteristics of HFD-induced microglial priming remain unclear. We aim to investigate how HFD-induced microglial priming, followed by a lipopolysaccharide (LPS) challenge, affects brain functions.
    METHODS: Male Wistar rats were divided into control, unprimed, and primed groups. The primed groups received either a single LPS injection (0.5 mg/kg, intraperitoneally) or HFD consumption for 4-8 weeks. Following the priming phase, all rats (except controls) were subjected to an LPS challenge with a 4- or 8-week interval. After 24 h of LPS challenge, cognition, anxiety-, and depressive-like behaviors were assessed. The brain and hippocampus were collected for further analysis.
    RESULTS: Both LPS- and 4-week HFD-primed groups, followed by LPS challenge, exhibited increased peripheral and brain oxidative stress, impaired neurogenesis, disrupted neurotransmitter balance, and altered glycolysis and Krebs cycle substrates. These changes also caused microglial morphological alterations, elevated C1q levels, and synaptic loss, which were associated with anxiety- and depressive-like behaviors, indicating that 4-week HFD consumption has a similar immune priming ability to a single dose of LPS injection. Extending HFD priming to 8 weeks exacerbated microglial and brain inflammation, synaptic loss, and behavioral deficits. Furthermore, prolonging the interval between priming and LPS challenge worsened inflammation and cognitive decline, suggesting the persistent effects of microglial priming.
    CONCLUSIONS: HFD consumption persistently and time-dependently primes microglia similar to a single LPS injection, influencing immune responses and contributing to behavioral abnormalities.
    Keywords:  C1q complement; anxiety; cognition; depression; high‐fat diet; synaptic engulfment
    DOI:  https://doi.org/10.1111/apha.70060
  61. Adv Clin Exp Med. 2025 May 23.
    Lectins and neurodegeneration: A glycobiologist's perspective.
    Beata Olejnik, Mirosława Ferens-Sieczkowska.
      Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, affect an increasing number of people in aging societies, dramatically reducing the quality of life of those affected. Hence, intensive research efforts are aimed at understanding the molecular mechanisms of the disease progress, with the hope for developing effective therapeutic strategies. The progress of neurodegenerative diseases is associated with a complex activity of the immune system in the brain tissue. Carbohydrate-binding proteins (lectins) play a key role in the inflammation-related activation of microglia. Siglecs, maintained in an active state by binding to sialic acid-terminated glycoconjugates, help establish homeostasis by protecting nerve cells from phagocytosis and preventing triggering receptor expressed on myeloid cells 2 (TREM2) activation. Upon activation, microglia release sialidase, an enzyme that cleaves sialic acid residues from glycoconjugates, thereby exposing galactose as the next monosaccharide in the glycan chain. After losing siglec-mediated protection, the glycan becomes a ligand for Galectin-3 (Gal-3). Overexpression of this lectin under inflammatory conditions activates TREM2 and TLR4 signaling pathways, enhances the phagocytic activity of microglia and leads to tissue damage. Blocking Gal-3 interactions with the thiodigalactoside inhibitor (TD-139) appears to be a promising novel approach to pharmacologically alleviating neuroinflammation.
    Keywords:  Siglec; galectin; glycosylation; microglia; neurodegeneration
    DOI:  https://doi.org/10.17219/acem/204107
  62. Neurochem Res. 2025 May 23. 50(3): 170
    The Ubiquitination and Degradation of SH2B3 Mediated by MEF2A/WWP2 Axis Restores Microglial Homeostasis to Alleviate Cerebral Microvascular Endothelial Cell Injury in Ischemic Stroke.
    Si-Xian Lin, Chenglong Shi, Lei Zhao, Lei Xian, Wenwu Yang, Zhenyu Wang, Longjie Qin, Xiao-Li Min, Jiasheng Yu.
      Ischemic stroke (IS) is a severe disease. The altered activation states of microglia play important roles in IS. In present study, a total of 125 C57BL/6 mice was used (N = 6 per group). Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) were performed for in vivo and in vitro model construction. The infarct size was detected using TTC staining. The nerve injury was evaluated by a neurological deficit score. OGD-treated brain microvascular endothelial cells (BMECs) were co-cultured with BV2 cells. Cell viability was determined by CCK-8 assay, and the apoptosis rate was identified by flow cytometry analysis. Transendothelial electronic resistance (TEER) of the cells was measured by TEER measurement. Molecular interactions were analyzed using dual-luciferase reporter gene, ChIP, and Co-IP assays. All in vitro experiments were conducted with three replicates, and each experiment was performed in triplicate. We found that Src Homology 2B Adaptor Protein 3 (SH2B3) was overexpressed in the cerebral cortex tissues of MCAO treated mice (P < 0.01), and BMECs co-cultured with BV-2 cells under OGD conditions (P < 0.01). SH2B3 knockdown or Myocyte Enhancer Factor 2 A (MEF2A) overexpression reduced infarct size and improved neurological function in MCAO mice. SH2B3 knockdown enhanced OGD-treated cell viability (P < 0.05), inhibited cell apoptosis (P < 0.05) in BMECs, and ameliorated BBB (P < 0.01). Moreover, SH2B3 knockdown changed the activation status of microglia. MEF2A promoted the transcriptional activation of WW Domain Containing E3 Ubiquitin Protein Ligase 2 (WWP2) and WWP2 promoted the ubiquitination and degradation of SH2B3. SH2B3 overexpression reversed the effects of MEF2A overexpression on microglia states, BMECs injury and BBB function. In summary, MEF2A promoted the ubiquitination-mediated degradation of SH2B3 via transcription up-regulating WWP2, then changed the activation status of microglia, thus ameliorating BMEC injury, and finally ameliorating IS injury.
    Keywords:  Blood-brain barrier; Ischemic stroke; MEF2A; Microglia polarization; SH2B3
    DOI:  https://doi.org/10.1007/s11064-025-04406-x
  63. Stress. 2025 Dec;28(1): 2502742
    Electroacupuncture improves sleep deprivation-induced cognitive impairment by suppressing hippocampal inflammatory response in mice.
    Guoyan Li, Jingbo Liu, Kejing Zhang.
      Sleep deprivation (SD) is known to induce neurocognitive dysfunction, with hippocampal inflammation emerging as a critical mediator. Electroacupuncture has shown efficacy in modulating inflammation in neurological disorders, but its potential in mitigating SD-induced cognitive impairment remains underexplored. Using a murine model, we investigated the effects of electroacupuncture on hippocampal inflammation and cognitive function following SD treatment. BALB/c mice underwent sleep disruption using a multiple-platform apparatus and were subsequently treated with electroacupuncture. Cognitive function was assessed using the Morris Water Maze and Y-maze tests. Electroacupuncture treatment significantly ameliorated SD-induced cognitive impairment, as evidenced by improved performance in spatial memory tasks. Additionally, electroacupuncture attenuated hippocampal inflammation, characterized by reduced levels of pro-inflammatory cytokines (IL-1β, MCP-1 and TNF-α) and increased expression of the anti-inflammatory cytokine IL-10. Mechanistically, electroacupuncture suppressed microglial activation and inhibited the TLR4/NF-κB signaling pathway within the hippocampus. Electroacupuncture has therapeutic potential in mitigating SD-induced cognitive dysfunction by modulating hippocampal inflammation, which offers a promising non-pharmacological approach for preserving cognitive function in sleep-deprived individuals.
    Keywords:  Electroacupuncture; cognitive impairment; hippocampal inflammation; sleep deprivation
    DOI:  https://doi.org/10.1080/10253890.2025.2502742
  64. Phytomedicine. 2025 May 16. pii: S0944-7113(25)00418-0. [Epub ahead of print]142 156780
    Schisandrin B ameliorates Alzheimer's disease by suppressing neuronal ferroptosis and ensuing microglia M1 polarization.
    Tao Ding, Meiying Song, Yongshi Wu, Zhu Li, Shanshan Zhang, Xiang Fan.
       BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal damage, with poor prognosis and limited therapeutic options. Inhibition of neuronal ferroptosis has shown promise as a potential treatment for AD. Schisandrin B (Sch B), a major active component of Schisandra chinensis, exhibits potential neuroprotective effects. However, whether Sch B inhibits neuronal ferroptosis remains unclear.
    PURPOSE: To investigate the mechanisms underlying the effects of Sch B on the GSK3β/Nrf2/GPX4 and FSP1 signaling pathways, which are the suppression of neuronal ferroptosis and the potential therapeutic intervention in AD.
    METHODS: We employed the 3 × Tg mouse model in vivo, and utilized the erastin-induced ferroptosis model in SH-SY5Y/APP695swe cells in vitro. Nissl staining was conducted to facilitate histopathological assessment. Assessment of neuronal ferroptosis was performed utilizing a lipid peroxidation and ferroptosis marker assay kit. Furthermore, bioinformatic analysis was executed with the application of the GEO database. Immunofluorescence and Western blot analyses were performed to quantify protein expression levels within the cellular context. ELISA was utilized to determine cytokine concentrations within the supernatant of cell cultures. RT-PCR was executed to evaluate mRNA expression levels.
    RESULTS: Sch B suppresses the activation of GSK3β, modulating the Nrf2/GPX4 signaling pathway and consequently inhibiting ferroptosis in neurons, which results in amelioration of cognitive impairment and pathological damage in 3 × Tg mice. Sch B also inhibits GSK3β activation, thereby modulating the Nrf2/GPX4 signaling pathway to prevent erastin-induced ferroptosis in SH-SY5Y695swe cells in vitro. Furthermore, Sch B modulates FSP1, enhancing its synergistic interaction with the GSK3β/Nrf2/GPX4 pathway to suppress neuronal ferroptosis. Sch B can also inhibit TNF-α release from neurons undergoing ferroptosis, thus impeding the activation of M1-type microglia, suggesting a multifaceted neuroprotective strategy against neuroinflammatory processes.
    CONCLUSION: Sch B modulates the GSK3β/Nrf2/GPX4 pathway in conjunction with FSP1 to inhibit neuronal ferroptosis and the subsequent microglial M1 polarization mediated by neuronal ferroptosis, thereby improving cognitive impairment and pathological damage in AD.
    Keywords:  Alzheimer's disease; FSP1; Ferroptosis; GSK3β; Polarization of microglia; Schisandrin B
    DOI:  https://doi.org/10.1016/j.phymed.2025.156780
  65. Cell Death Discov. 2025 May 20. 11(1): 243
    TREM2 deficiency exacerbates cognitive impairment by aggravating α-Synuclein-induced lysosomal dysfunction in Parkinson's disease.
    Baoyu Zhu, Jiezhu Feng, Xiaomei Liang, Zhongling Fu, Mengshi Liao, Tongtong Deng, Kaicheng Wang, Jianwei Xie, Jieshan Chi, Lu Yang, Yuyuan Gao, Kun Nie, Lijuan Wang, Piao Zhang, Yuhu Zhang.
      Cognitive impairment in Parkinson's disease (PD) is a widespread and rapidly progressive feature that impacts prognosis. Although TREM2 has been implicated in neuroprotection across various neurodegenerative diseases, its specific role in PD remains to be clarified. In this study, we first detected the hippocampus of human PD specimens and of the mutant A53T α-Synuclein transgenic mice (A53T mice), and found a significant increase in the number of TREM2+ microglia. To evaluate the effects of TREM2 deficiency, TREM2-deficient A53T mice (TREM2-/-/A53T mice) were generated. In these mice, exacerbated cognitive impairment, neurodegeneration, disruption of synaptic plasticity, and accumulation of pathological α-Synuclein (α-Syn) in the hippocampus were observed, without any detected motor dysfunction. Despite increased infiltration of activated microglia surrounding α-Syn aggregates, lysosomal dysfunction in microglia was aggravated in the TREM2-/-/A53T mice. In addition, transcriptional analyses and in vitro experiments further found that TREM2 knockdown inhibited the nuclear distribution of TFEB via the ERK1/2 pathway, exacerbating α-Syn-induced lysosomal dysfunction and causing more pathological α-Syn accumulation. Finally, HT22 cells were cocultured with TREM2 knockdown of BV-2 cells pretreated with recombinant human A53T α-Syn preformed fibrils (PFFs). The coculture experiments showed that TREM2 knockdown in BV-2 cells pretreated with PFFs enhanced the phosphorylation of α-Syn and promoted apoptosis in HT22 cells via inhibiting α-Syn degradation. In conclusion, TREM2 deficiency exacerbates cognitive impairment in PD by exacerbating α-Syn-induced microglial lysosomal dysfunction, identifying TREM2 as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41420-025-02538-1
  66. J Transl Med. 2025 May 23. 23(1): 580
    Chronic mild stress disrupts mitophagy and mitochondrial status in rat frontal cortex.
    Cristina Ulecia-Morón, Álvaro G Bris, Karina S MacDowell, José L M Madrigal, Borja García-Bueno, Juan C Leza, Javier R Caso.
       BACKGROUND: Mitochondria are very dynamic organelles that maintain cellular homeostasis, crucial in the central nervous system. Mitochondrial abnormalities have been described in neuropsychiatric diseases, namely major depression disorder (MDD) and schizophrenia. Since stress is the predominant non-genetic cause of MDD, and has a direct impact on mitochondrial networks, understanding how psychological stress affects mitochondrial health is vital to improve the current pharmacological therapies.
    METHODS: The effect of 21 days of unpredictable stress was evaluated in frontal cortex of Wistar male rats comparing protein and gene markers of mitophagy (PINK1, PARKIN, BNIP3, NIX, FUNDC1), mitochondrial biosynthesis (PGC1α, NRF1, TFAM) and dynamics (MFN1, MFN2, OPA1, DRP1), and mitochondrial presence within microglia with the MitoTracker Green FM™ probe.
    RESULTS: Chronic mild stress (CMS) caused the upregulation of mitochondrial mass, mitochondria depolarization, dysregulation in mitochondrial dynamics towards fusion, the increase of mitophagy markers and the induction of genes that activate mitochondrial biogenesis in frontal cortex. CMS also promoted microglia recruitment and mitochondrial number boosting within them.
    CONCLUSIONS: There is a dysregulation of mitochondrial dynamics towards fusion, an upregulation of mitophagy markers, and the induction of genes associated with mitochondrial biogenesis in response to CMS in the frontal cortex of adult rats. This study highlights the impact of psychological stress on brain mitochondrial networks.
    Keywords:  Chronic mild stress (CMS); Microglia; Mitochondria; Mitophagy; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12967-025-06604-1
  67. Neuroscience. 2025 May 16. pii: S0306-4522(25)00385-9. [Epub ahead of print]
    Schaftoside restrains neuroinflammation and ameliorates cerebral ischemic injury associated with LncGm36 mediated COP1 upregulation.
    Ermei Lu, Jie Chen, Qiaoyun Wu, Jiayu Wu, Kecheng Zhou.
      Schaftoside(SS), a bioactive compound derived fromHerba Desmodii Styracifolii, has demonstrated anti-inflammatory properties in microglial cells; However, its role in ischemic brain injury in mice remains unclear. This study aimed to investigate the neuroprotective effects of schaftoside in a mouse model of middle cerebral artery occlusion (MCAO) and elucidate the underlying molecular mechanism. RNA sequencing revealed that schaftoside significantly upregulated the long noncoding RNA Gm32496 (LncGm36), which was prominently downregulated in the ischemic penumbra of MCAO mice. Administration of schaftoside reduced the infarct size, alleviated brain edema, and improved neurological outcomes in MCAO mice through LncGm36 upregulation. Mechanistically, schaftoside-induced LncGm36 expression was accompanied by elevated levels of COP1, a key regulator involved in neuroinflammation. RNA pull-down assays confirmed a direct interaction between LncGm36 and COP1. Silencing of either LncGm36 or COP1 attenuated schaftoside-mediated anti-inflammatory microglial polarization and neuroprotection. Collectively, these results indicate that schaftoside confers neuroprotection against ischemic brain injury by promoting an anti-inflammatory phenotypic shift of microglia through the LncGm36/COP1 pathway, suggesting its potential as a therapeutic agent for ischemic stroke.
    Keywords:  Ischemic brain injury; Microglial polarization; Neuroinflammation; Neuroprotection; Schaftoside
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.05.023
  68. J Neuroimmunol. 2025 May 18. pii: S0165-5728(25)00125-0. [Epub ahead of print]405 578644
    Anti-IL-6R antibody treatment changes microglial phenotype in AQP4 peptide-immunized mice, leading to suppression of myelitis severity.
    Shota Miyake, Yoshichika Katsura, Masayuki Baba, Haruna Tomizawa-Shinohara, Yoshihiro Matsumoto, Kenichi Serizawa.
      Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by periods of remission and relapse; severe relapses often lead to permanent neurological disability. Satralizumab, an anti-interleukin-6 receptor (anti-IL-6R) antibody, has been proven in previous studies to reduce the frequency and severity of relapses in patients with NMOSD. There are several reports on the mechanisms through which anti-IL-6R antibodies are thought to suppress relapse. However, the mechanisms underlying how anti-IL-6R antibodies reduce the severity of myelitis have not been elucidated. We investigated the effect of an anti-IL-6R antibody (MR16-1) on the severity of myelitis in an AQP4 peptide-immunized mice model. This mouse model exhibits NMOSD-like pathological characteristics and the production of anti-AQP4 autoantibodies. Unlike the previously reported experimental protocol where antibody and peptide are administered simultaneously, we tested delayed administration of MR16-1 (9 days after peptide immunization). We found that delayed MR16-1 administration suppressed the clinical score of AQP4 peptide-immunized mice experiencing myelitis. Mice treated with MR16-1 showed a greater percentage of CD11c+ microglia in the spinal cord, along with upregulated expression of phagocytosis-related genes. Blockade of IL-6R by anti-IL-6R antibodies may suppress the severity of myelitis by increasing CD11c+ microglia and enhancing phagocytic function in AQP4 peptide-immunized mice.
    Keywords:  Anti-IL-6 receptor antibody; Aquaporin-4; IL-6; Microglia; NMOSD
    DOI:  https://doi.org/10.1016/j.jneuroim.2025.578644
  69. J Neuroimmune Pharmacol. 2025 May 20. 20(1): 56
    Clonidine Ameliorates Neuroinflammation in the Rat Model of Tourette Syndrome.
    Zhongling Ke, Yuxian Huang, Ang Wang, Yanhui Chen.
      Neuroinflammation plays a vital role in the etiology and pathogenesis of Tourette syndrome (TS). The postmortem report of TS patients clarified that IL-2 is elevated in the basal ganglia region, supporting neuroinflammation of TS. α2 receptor agonist (clonidine) is one of the primary drugs for treating tic disorders; supported by clinical and animal experiments, α2 receptor agonists have potential anti-inflammatory effects. This article aims to explore the impact of clonidine on neuroinflammation with TS and to reveal the possible mechanism of clonidine-mediated neuroinflammation with TS. Thirty P21 SD rats were randomly divided into a TS rat group (n = 20) and a normal control group (n = 10). After successful TS modelling, rats were randomly divided into the clonidine intervention group (n = 10) and the TS group (n = 10). The clonidine intervention group received clonidine 0.1 mg/kg by gavage daily for seven consecutive days. After behavioural evaluation on day 8, the brain was removed from the head. The striatum was separated from one side of the brain and subjected to ELISA to detect cytokines. The other side of the brain was subjected to immunohistochemical detection for microglial activation, and the integral optical density value was calculated using image software for comparison between the groups. Compared to the normal group, IL-2 cytokine levels in TS rats were significantly higher (P < 0.05). In the clonidine group, IL-2 levels (213.82 ± 121.48 pg/ml) were significantly lower than in the TS group (322.61 ± 79.27 pg/ml) (P < 0.05) but not significantly different from the normal control group (257.40 ± 95.80 pg/ml) (P > 0.05). Immunohistochemical analysis showed significant microglial activation in TS rats (IOD = 22.10 ± 6.67) compared to the normal group (IOD = 11.58 ± 4.36) (P < 0.05). Clonidine administration reduced microglial activation, with a significant difference between the TS + clonidine group (IOD = 15.97 ± 8.03) and TS rats (P < 0.05). Clonidine can suppress the neuroinflammatory response in Tourette syndrome, and its inhibitory effect on the neuroinflammatory response may be a potential beneficial effect of this treatment.
    Keywords:  Clonidine; Cytokines; Microglia; Neuroinflammation; Tourette syndrome
    DOI:  https://doi.org/10.1007/s11481-025-10214-5
  70. Clin Sci (Lond). 2025 May 20. pii: CS20242965. [Epub ahead of print]
    Increased absorptive transcytosis and tight junction weakness in heart failure are equally corrected by exercise training and losartan.
    Hiviny de Ataides Raquel, Mariana Makuch-Martins, Sany M Perego, Gustavo S Masson, Leonardo Jensen, Lisete C Michelini.
      Reduced ventricular function, renin-angiotensin system upregulation and sympathoexcitation are hallmarks of heart failure (HF). Recently we showed that blood-brain barrier (BBB) lesion within autonomic nuclei contributes to autonomic imbalance and that exercise training (T) normalizes BBB function and improves autonomic control. We sought now to identify the mechanism( involved in both HF-induced lesion and exercise-induced correction. Wistar rats submitted to coronary artery ligation were, after the development of HF, assigned to losartan (Los) or vehicle (Veh) treatments and simultaneously submitted to T or sedentary ( protocol. After hemodynamic/autonomic recordings and evaluation of BBB permeability, brains were harvested for ultrastructural analyses of the barrier (tight junctions (TJ) tightness and vesicles trafficking) within capillaries of the hypothalamic paraventricular nucleus. Local angiotensin II (Ang II) expression and activation of microglial cells (IBA-1 immunofluorescence) were also evaluated. High sympathetic activity and pressure variability, reduced parasympathetic control of the heart, elevated BBB permeability, high vesicular trafficking and TJ weakness exhibited by Veh-rats were equally corrected in Veh-T, Los-and Los-T groups. The increased PVN Ang II expression and IBA-1 density in Veh-group were similarly reduced by T, Los and combination of both. Ang II, colocalized with microglia AT1 receptors, induced their remodeling from disease-associated phenotype in Veh-S rats to homeostatic-surveilling conditions in the other groups. All measured parameters exhibited strong correlations with Ang II availability. Data indicated that changes in PVN Ang II availability induced by HF, exercise and losartan is the key regulator of transcellular and paracellular transport across the BBB.
    Keywords:  absorptive transcytosis; angiotensin II; blood-brain barrier; heart failure; microglia; tight junctions
    DOI:  https://doi.org/10.1042/CS20242965
  71. Mol Neurobiol. 2025 May 17.
    Cold-Induced RNA-Binding Protein (CIRP) Affects Cerebral Ischemia-Reperfusion Injury Through NF-κB Pathway.
    Yong Fan, Jingjing Wei, Lili Lin, Jinying Lin, Xiaohua Li, Liyu Xu, Xiaohui Zhou, Yongkun Li, Yongkai Yang.
      The pathological and physiological mechanisms for effectively mitigating ischemia-reperfusion (I/R) injury and preserving brain structure and function remain unclear. This study investigates the regulatory mechanism underlying cold-induced RNA-binding protein (CIRP)-mediated NF-κB pathway in cerebral I/R injury and neuronal inflammatory injury. The infarct volume of I/R CIRP-/- mice was significantly mitigated, and the inflammatory factor IL-18 expression in mice serum and the NLRP3 and IL-1β expression in brain tissue was significantly decreased as opposed to the I/R WT mice. The in vitro outcomes manifested that inhibiting CIRP expression led to a significant hindrance in cell apoptosis, a significant drop in the inflammatory factors levels in the cell supernatant, and a significant decline in the expression of pyroptosis-linked proteins ASC, cleaved caspase-1, and gasdermin D (GSDMD) in cells. Following administration of the NF-κB pathway inhibitor PDTC, there was a significant hindrance in cell apoptosis, as well as a significant drop in the inflammatory factors levels IL-1β, TNF-α, and IL-18 in the cell supernatant. After treating BV-2 cells with HT22 cell conditioned medium under OGD condition, the content of LDH in BV-2 cells was increased. Intervention of CIRP expression in HT22 cells resulted in reduced damage to BV-2 cells and decreased expression of M1 marker CD86. CIRP may be involved in neuronal damage in I/R and in vitro OGD models via the NF-κB /NLRP3 pathway, and it may affect microglial polarization.
    Keywords:  CIRP; MCAO/R; NF-κB/NLRP3 pathway; Polarization of microglia
    DOI:  https://doi.org/10.1007/s12035-025-05029-7
  72. Mol Brain. 2025 May 21. 18(1): 46
    Targeting CD74 in microglia to modulate experimental cerebral ischemia and reperfusion injury: insights from Single-Cell and bulk transcriptomics.
    Chang Cao, Ting Liu, Lu Peng, Lianxin Li, Zhongmou Xu, Xiang Li, Gang Chen, Haiying Li, Lei Bai.
      Ischemic stroke remains a leading cause of mortality and long-term disability, with reperfusion injury contributing significantly to poor clinical outcomes. Microglia, the primary immune cells of the central nervous system, play a dual role in ischemic stroke by both exacerbating injury through neuroinflammation and supporting recovery through neuroprotection. This study aimed to explore the role of CD74, a gene upregulated in microglia following ischemia-reperfusion injury. Using single-cell RNA sequencing and bulk RNA sequencing, we identified CD74 as a potential target involved in microglial-mediated neuroinflammation. We observed a significant increase in CD74 expression in microglia following middle cerebral artery occlusion/reperfusion (MCAO/R), which correlated with pro-inflammatory cytokine production and neuroinflammation. Targeted knockdown of CD74 in microglia using CX3CR1Cre/ERT2 mice led to a reduction in infarct volume, inflammatory cytokine levels, and long-term neurological deficits. Behavioral tests showed improved motor coordination, sensory function, and exploratory behavior in CD74 knockdown mice. These results suggest that CD74 is a critical mediator of microglia-driven neuroinflammation, and targeting CD74 may represent a promising therapeutic strategy for reducing ischemic brain injury and promoting recovery after stroke.
    DOI:  https://doi.org/10.1186/s13041-025-01197-8
  73. Stem Cell Res Ther. 2025 May 22. 16(1): 256
    Autophagy modulation by hADSCs and green light therapy alleviates inflammation and promotes functional recovery after spinal cord injury.
    Junjie Chen, Quanxin He, Huan Xie, Bin Gu, Liyi Zhou, Daoyuan Jiang, Hongxin Xie, Li Liang, Zhilai Zhou, Hui Zhang.
       BACKGROUND: Spinal cord injury (SCI) results in chronic motor deficits and intractable neuropathic pain, driven by neuroinflammation and impaired tissue repair. Current therapies inadequately address these multifaceted challenges. This study investigated the therapeutic effects of human adipose-derived mesenchymal stem cells (hADSCs) transplantation combined with green light (GL) therapy to modulate inflammation, enhance autophagy, and facilitate functional restoration post-SCI.
    METHODS: In a murine SCI model, hADSCs (1 × 106 cells) were intraspinally delivered with concurrent GL irradiation (100 lux, 8 h/d). Behavioral assessments included footprint analysis, von Frey test, and thermal hyperalgesia testing. Histological analyses included Luxol Fast Blue (LFB), Nissl, Masson, and hematoxylin and eosin (HE) staining for myelin integrity, neuronal survival and glial scar area. Immunofluorescence, ELISA and qPCR were used to assess inflammation, and autophagy-related proteins were analyzed using immunofluorescence and western blotting. The role of microglial autophagy was investigated by inhibiting autophagy using 3-methyladenine (3MA).
    RESULTS: The combined treatment group (hADSCs + GL) showed significant motor function recovery, pain relief, and histological improvement, outperforming either treatment alone. Histological analyses revealed enhanced myelin preservation, reduced glial scar formation, and increased neuronal survival. Quantitative analysis revealed that TNF-α, IL-1β, and CD68 expression in the combined treatment group were markedly lower than those in single-treatment cohorts (P < 0.05). Furthermore, the combined treatment promoted microglia autophagy, evidenced by increased Beclin1 and LC3B expression and decreased P62 in microglia. Inhibition of autophagy with 3MA reversed the anti-inflammatory benefits of the combined therapy, exacerbating the inflammatory response.
    CONCLUSIONS: The combined treatment of hADSCs transplantation and GL therapy significantly improves functional recovery and reduces inflammation following SCI. The therapeutic effects are mediated in part by the modulation of microglial autophagy.
    Keywords:  Adipose-derived mesenchymal stem cells; Autophagy; Green light; Neuropathic pain; Spinal cord injury
    DOI:  https://doi.org/10.1186/s13287-025-04367-6
  74. Phytomedicine. 2025 May 14. pii: S0944-7113(25)00504-5. [Epub ahead of print]143 156866
    Evodiamine inhibits NLRP3 inflammasome-mediated microglial pyroptosis and promotes remyelination via SLC2A4-regulated autophagy.
    Yunjie Zhao, Xingzong Sun, Faling Shao, Lin Li, Weilie Xiao, Chengyang Gu, Yunqian Zhang, Yue Jia, Lili Dai, Hongliang Li, Hongkun Bao.
       BACKGROUND: Activation of the NLRP3 inflammasome triggers pyroptosis, a pro-inflammatory type of cell death, in multiple sclerosis (MS). Evodiamine (EVO) possesses anti-inflammatory and neuroprotective properties; however, its potential molecular and signaling pathways in MS remain to be elucidated. This study aimed to explore the therapeutic potential of EVO for remyelination in MS and elucidated its underlying mechanisms.
    METHODS: We utilized cuprizon (CPZ)/experimental autoimmune encephalomyelitis (EAE)-induced demyelinated mice and lipopolysaccharide+adenosine triphosphate (LPS+ATP)-induced pyroptosis of BV2 cells to investigate the potential of EVO in MS treatment. Various analyses were conducted, including rotarod fatigue test, RNA sequence, luxol fast blue, molecular docking, SPR, immunoblotting, qRT-PCR, immunofluorescence, and transmission electron microscopy, to analysis the targets and signaling pathways involved in EVO treatment.
    RESULTS: EVO emerged as a promising remyelination agent in the CPZ/EAE demyelination models, acting through SLC2A4. Regarding its mechanism, EVO inhibited NLRP3 inflammasome-mediated microglial pyroptosis through SLC2A4 regulation of autophagy during demyelinating disease, but this change was reversed by SLC2A4 inhibitor PGF2α in vivo. Additionally, EVO inhibited LPS+ATP-induced pyroptosis of BV2 cells by preventing NLRP3 inflammasome activity and cleavage of the pyroptosis executive protein gasdermin D. It also promoted autophagy and inhibited NLRP3 inflammasome-mediated pyroptosis in BV2 cells via SLC2A4. Furthermore, an autophagy inhibitor 3-methyladenine reversed the inhibitory effect of EVO on NLRP3 inflammasome-mediated pyroptosis in BV2 cells.
    CONCLUSION: The present study demonstrated that EVO inhibits NLRP3 inflammasome-mediated microglial pyroptosis and promotes remyelination via SLC2A4-regulated autophagy during demyelinating disease, which suggests EVO as a promising drug candidate for the treatment of MS.
    Keywords:  Autophagy; Evodiamine; NLRP3 inflammasome; Pyroptosis; SLC2A4
    DOI:  https://doi.org/10.1016/j.phymed.2025.156866
  75. J Neurol Neurosurg Psychiatry. 2025 May 16. pii: jnnp-2025-336063. [Epub ahead of print]
    Plasma CHI3L1 associates with brain volume loss and glial activation in multiple sclerosis.
    Venla Ahola, Maija Saraste, Marjo Nylund, Markus Matilainen, Amelie Luoma, Anna Vuorimaa, Jussi Lehto, Sini Laaksonen, Eeva-Christine Brockmann, Jens Kuhle, David Leppert, Tero Soukka, Urpo Lamminmäki, Laura Airas.
       BACKGROUND: Multiple sclerosis (MS) progression independent of relapses is driven by brain innate immune cell activation. The aim of this study was to evaluate the association between chitinase-3-like protein 1 (CHI3L1), expressed in brain by astrocytes and microglia, measured from blood and smouldering inflammation measured using 18 kDa translocator protein (TSPO) positron emission tomography (PET) in patients with MS.
    METHODS: The study cohort included 55 patients with MS (25 progressive MS (PMS) and 30 relapsing remitting MS (RRMS)) and 17 healthy controls (HC). CHI3L1 was measured with commercial ELISA from plasma samples. A subcohort (44 MS and 9 HC) underwent TSPO-PET to assess [11C]PK11195 distribution volume ratio (DVR) and MRI concurrent to blood sampling. These imaging outcomes were used in respective correlation and linear regression analyses.
    RESULTS: CHI3L1 concentration in plasma was higher in PMS (23.5 ng/mL) compared with HC (16.8 ng/mL, p=0.0055) and RRMS (19.3 ng/mL, p=0.049). CHI3L1 associated with brain [11C]PK11195 DVR in all MS (standardised estimate 0.89, 95% CI 0.23 to 1.55, p=0.010) and in PMS (Spearman correlation ρ=0.58, 95% CI 0.058 to 0.86, p=0.032). Additionally, CHI3L1 was associated with smaller brain volume in both MS (-0.75, -1.38 to -0.11, p=0.023) and PMS (ρ=-0.56, -0.83 to -0.095, p=0.021). Furthermore, CHI3L1 was associated with Expanded Disability Status Scale (0.70, 0.12 to 1.28, p=0.019) and age (0.93, 0.37 to 1.48, p=0.002) among all patients with MS.
    CONCLUSIONS: Association of CHI3L1 with glial activation and brain volume loss identifies plasma CHI3L1 as a promising biomarker for smouldering inflammation and MS progression-related pathology.
    Keywords:  MRI; MULTIPLE SCLEROSIS; NEUROIMMUNOLOGY; PET
    DOI:  https://doi.org/10.1136/jnnp-2025-336063
  76. Cell Biol Toxicol. 2025 May 20. 41(1): 86
    Neuron-like macrophage differentiation via the APOE-TREM2 axis contributes to chronic pain in nasopharyngeal carcinoma.
    Hongxi Li, Lanqing Zhao, Jinwei Li, Kailin Zhang, Weiliang Bai, Yu Chen.
      Chronic pain is a prevalent and debilitating symptom in patients with nasopharyngeal carcinoma (NPC). Fresh insights indicate that tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) may undergo neuron-like differentiation, potentially contributing to pain mechanisms. By examining the apolipoprotein E (APOE) together with the triggering receptor expressed on myeloid cells 2 (TREM2), this study aims to clarify their joint function in modulating differentiation and how this interplay might be implicated in chronic pain associated with NPC. Through comprehensive analysis using TCGA-NPC transcriptomic datasets and single-cell RNA sequencing (scRNA-seq), we assessed the molecular landscapes of both NPC-affected and healthy nasopharyngeal tissues. Differential gene expression and immune cell profiling identified macrophages as key players in the inflammatory response. Single-cell sequencing revealed a distinct subpopulation of neuron-like macrophages expressing neurogenesis-related genes. Macrophage-to-neuron-like cell transformation in response to NPC cells was examined through in vitro co-culture systems, highlighting the involvement of the APOE-TREM2 regulatory pathway. In vivo studies involved macrophage depletion and TREM2 knockdown in mouse models to evaluate the impact on chronic pain development. Infiltrating macrophages were significantly more abundant in NPC samples, with many exhibiting neuron-like features that were positively linked to high levels of WNT5 A expression. In vitro, NPC cells induced macrophage differentiation into neuron-like cells, a process regulated by TREM2 and APOE. TREM2 knockdown in macrophages resulted in a reduction of chronic pain behaviors in mouse models, highlighting the contribution of the APOE-TREM2 Axis to NPC-associated chronic pain. Our findings demonstrate that NPC cells promote macrophage reprogramming through the APOE-TREM2 Axis, leading to neuron-like differentiation and contributing to chronic pain in NPC patients. Targeting this pathway may offer novel therapeutic strategies for managing chronic pain in NPC.
    Keywords:  Chronic pain; Nasopharyngeal carcinoma; Neuron-like macrophages; Single-cell sequencing; TCGA; TREM2
    DOI:  https://doi.org/10.1007/s10565-025-10035-5
  77. Cell Rep Methods. 2025 May 13. pii: S2667-2375(25)00090-6. [Epub ahead of print] 101054
    An AAV capsid proposed as microglia-targeting directs genetic expression in forebrain excitatory neurons.
    Wenhao Cao, Zhiqun Tan, Bereket T Berackey, Jason K Nguyen, Sara R Brown, Shiyang Du, Bin Lin, Qiao Ye, Magdalene Seiler, Todd C Holmes, Xiangmin Xu.
      A newly developed capsid AAV-MG1.2 was reported to mediate specific microglial transduction. However, we find that AAV-MG1.2 actually enables specific genetic access to excitatory neurons in forebrain regions including hippocampal formation and visual cortex but does not confer expression in microglia or astrocytes in vivo. Furthermore, we find that AAV-MG1.2 specifically labels the deep layer of the CA1 pyramidal layer in a titer-dependent manner. We show that AAV-MG1.2-Cre can be used to genetically target excitatory neurons for cell-type-specific neural circuit mapping studies. We also find that AAV-MG1.2 conserves specificity for excitatory neurons in rat hippocampus. Thus, the AAV-MG1.2 presents a useful viral-genetic tool for targeting excitatory neurons in the forebrain across different species.
    Keywords:  AAV toolbox; AAV-MG1.2; CP: neuroscience; cross-species; excitatory neurons; hippocampus; neocortex; neural circuit tracing; tool development
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101054
  78. ACS Appl Mater Interfaces. 2025 May 19.
    Mesenchymal Stem-Cell-Derived Exosomes Loaded with Phosphorus Dendrimers and Quercetin Treat Parkinson's Disease by Modulating Inflammatory Immune Microenvironment.
    Lu Zhang, Mengsi Zhan, Huxiao Sun, Yu Zou, Regis Laurent, Serge Mignani, Jean-Pierre Majoral, Xueyan Cao, Mingwu Shen, Xiangyang Shi.
      The intricate pathologic features of Parkinson's disease (PD) coupled with the obstacle posed by the blood-brain barrier (BBB) significantly limit the efficacy of most medications, leading to difficulties in PD treatments. Herein, we have developed a nanomedicine based on stem-cell-derived exosomes coloaded with hydroxyl-terminated phosphorus dendrimers (AK76) and quercetin (Que) for combined therapeutic intervention of PD. The engineered nanocomplexes (for short, QAE NPs) exhibit an optimal size of 269.7 nm, favorable drug release profile, and desired cytocompatibility, enabling penetration of the nasal mucosa to accumulate in the brain without BBB crossing. The developed QAE NPs can scavenge reactive oxygen species, promote M2 microglial polarization, attenuate inflammation, and protect neurons by inducing autophagy and restoring mitochondrial homeostasis through the integrated anti-inflammatory and antioxidant properties of exosomes, Que and AK76, collectively leading to improved motor functions, coordination, and alleviation of depression-like symptoms in PD mice. The formulated QAE NPs combined with several therapeutic components are able to simultaneously modulate both microglia and neurons, offering promising potential for the treatment of PD and other neurodegenerative disorders.
    Keywords:  Parkinson’s disease; autophagy promotion; exosomes; microglia M2 polarization; phosphorus dendrimers
    DOI:  https://doi.org/10.1021/acsami.5c05809
  79. Neural Plast. 2025 ;2025 6103242
    Endogenous Recovery of Hippocampal Function Following Global Cerebral Ischemia in Juvenile Female Mice Is Influenced by Neuroinflammation and Circulating Sex Hormones.
    Jose J Vigil, Erika Tiemeier, James E Orfila, Nicholas E Chalmers, Victoria N Chang, Danae Mitchell, Isobella Veitch, Macy Falk, Robert M Dietz, Paco S Herson, Nidia Quillinan.
      Cardiac arrest (CA)-induced global cerebral ischemia (GCI) in childhood often results in learning and memory deficits. We previously demonstrated in a murine CA and cardiopulmonary resuscitation (CA/CPR) mouse model that a cellular mechanism of learning and memory, long-term potentiation (LTP), is acutely impaired in the hippocampus of juvenile males, correlating with deficits in memory tasks. However, little is known regarding plasticity impairments in juvenile females. We performed CA/CPR in juvenile (P21-25) female mice and used slice electrophysiology and hippocampal-dependent behavior to assess hippocampal function. LTP and contextual fear were impaired 7 days after GCI and endogenously recovered by 30 days. LTP remained impaired at 30 days in ovariectomized females, suggesting the surge in gonadal sex hormones during puberty mediates endogenous recovery. Unlike juvenile males, recovery of LTP in juvenile females was not associated with BDNF expression. NanoString transcriptional analysis revealed a potential role of neuroinflammatory processes, and specifically Cd68 pathways, in LTP impairment and hormone-dependent recovery. This was confirmed with staining that revealed increased Cd68 expression in microglia within the hippocampus. We were able to restore LTP in ovariectomized females with chronic and acute PPT administration, implicating estrogen receptor alpha in recovery mechanisms. This study supports a mechanism of endogenous LTP recovery after GCI in juvenile female mice, which differs mechanistically from juvenile males and does not occur in adults of either sex.
    Keywords:  cardiac arrest; endogenous recovery; estrogen receptor; neuroinflammation; synaptic plasticity
    DOI:  https://doi.org/10.1155/np/6103242
  80. Exp Neurol. 2025 May 16. pii: S0014-4886(25)00169-4. [Epub ahead of print]391 115305
    Salvianolic acid B exerts cerebroprotective effects after traumatic brain injury via Nrf2-dependent antioxidant and anti-inflammatory cascades.
    Dacheng Wang, Yanxia Geng, Fengming Gu, Yan Zhuang, Hai Lv, Xue He, Haicheng Yang, Jun Lu.
       BACKGROUND: Oxidative stress and inflammatory responses play crucial roles in the development of secondary brain injury following traumatic brain injury (TBI). Thus, this study aimed to investigate the potential cerebroprotective effects of salvianolic acid B (SalB) in mitigating oxidative stress and inflammatory responses post-TBI through the activation of Nrf2.
    PURPOSE: This study aims to investigate the potential cerebroprotective effects of SalB in ameliorating oxidative stress and inflammatory responses following TBI by activating Nrf2, thereby laying a foundation for TBI treatment.
    STUDY DESIGN: Controlled cortical impact and hydrogen peroxide were employed to replicate TBI in animal and cellular models, respectively.Behavioral studies predict neural function, Western Blot (WB) predicts oxidative stress, immunofluorescence and ELISA predict inflammatory response.The Nrf2 inhibitor ML385 was employed to investigate the involvement of the Nrf2 pathway in mediating the protective effects of SalB.
    METHODS: SalB was delivered via intraperitoneal injection 1 h after TBI induction, with its neuroprotective efficacy evaluated across a range of concentrations. In the cellular assay, SalB was used to incubate cells simultaneously with H2O2. WB analysis was employed to quantify protein levels, while malondialdehyde, glutathione, superoxide intensity, and reactive oxygen radical probes were utilized to evaluate oxidative stress. Immunofluorescence and ELISA techniques were used to characterize microglia phenotype and inflammatory response. Behavioral assays were also conducted to evaluate neurological function. The Nrf2 inhibitor ML385 was employed to investigate the involvement of the Nrf2 pathway in mediating the protective effects of SalB.
    RESULTS: Animal and cellular experiments indicate that SalB can mitigate oxidative stress through the Nrf2/Peroxiredoxin 2 pathway, and reduce inflammatory response via the Nrf2/Toll-like receptor 4/Myeloid differentiation primary response protein 88 pathway in a dose-dependent manner. Consequently, SalB demonstrates efficacy in enhancing neurological function following TBI. Conversely, the inhibitory effects of ML385 counteract the antioxidant and anti-inflammatory properties of SalB.
    CONCLUSIONS: SalB exerts its beneficial effects post-TBI through Nrf2-dependent antioxidants and as anti-inflammatory responses.
    Keywords:  Nrf2; SalB; TBI; TLR4/MyD88
    DOI:  https://doi.org/10.1016/j.expneurol.2025.115305
  81. JOR Spine. 2025 Jun;8(2): e70077
    In Vitro Validation of Pulsed Electromagnetic Field (PEMF) as an Effective Countermeasure Against Inflammatory-Mediated Intervertebral Disc Degeneration.
    Laura Guarnaccia, Laura Begani, Silvana Pileggi, Mauro Pluderi, Stefano Borsa, Claudia Fanizzi, Massimiliano Domenico Rizzaro, Giorgio Fiore, Laura Fontana, Rolando Campanella, Chiara Cordiglieri, Chiara Gaudino, Giovanni A Alotta, Monica Miozzo, Emanuele Garzia, Emanuela Barilla, Lorenzo Fassina, Laura Riboni, Marco Locatelli, Giovanni Marfia, Stefania E Navone.
       Background: Intervertebral disc (IVD) degeneration (IDD) is the main contributor to chronic low back pain (LBP), the leading cause of disability worldwide, with a significant impact on the quality of life and health of common people. The etiology of IDD is still unclear, but it has been largely demonstrated the crucial role of inflammation and neuroinflammation in the pathological and degenerative cascade of events characterizing IVD degeneration.
    Aim: In this study, we evaluated the potential therapeutic effect of pulsed electromagnetic field (PEMF) on human degenerated IVD (D-IVD) cells collected from patients who underwent discectomy.
    Materials & Methods: The experimental plan to test our hypothesis, involved viability assay, reactive oxide species/nitrite production, gene, and protein expression. To recapitulate the pro-inflammatory disc microenvironment occurring during IDD, interleukin-1β (IL-1β) was administered to IVD cell culture. Then, to dissect the contribution of neuroinflammatory condition to immune component, microglial cells were co-cultured with IVD-conditioned media, and viability and expression of inflammatory markers were detected.
    Results: Our data prove that in the IVD degenerative microenvironment, the increase of pro-inflammatory mediators, extracellular matrix degradative enzymes, and neuroinflammatory markers could be reduced by PEMF therapy, resulting in an overall improvement of degenerative condition and LBP.
    Conclusion: These results represent an impactful novelty for the management of people suffering from LPB, in terms of symptom relief and reduction of social-health system burden.
    Keywords:  inflammation; intervertebral disc degeneration; microglia; pilots; pulsed electromagnetic field; space
    DOI:  https://doi.org/10.1002/jsp2.70077
  82. J Neurointerv Surg. 2025 May 22. pii: jnis-2025-023108. [Epub ahead of print]
    Role of biliverdin reductase, a heme degradation pathway enzyme, in the development of vasospasm after subarachnoid hemorrhage.
    Zahra Hasanpour-Segherlou, Hunter Hutchinson, Haiyan Xu, Shawna Amini, Elizabeth Klaas, Melanie E Martinez, Brandon Lucke-Wold, Koji Hosaka, Brian Hoh.
       BACKGROUND: Subarachnoid hemorrhage (SAH) is a life-threatening condition with high mortality and significant neurological morbidity, often complicated by delayed cerebral ischemia (DCI) and vasospasm. Heme metabolites such as biliverdin (BV) are implicated in SAH-induced vascular dysfunction, yet the role of biliverdin reductase-A (BVR-A), an enzyme that reduces BV to bilirubin, remains underexplored. This study investigates the contribution of BV and oxidative post-translational modifications of BVR-A to vasospasm development.
    METHODS: We used a murine model of BV injection into the subarachnoid space and analyzed its effects on vasospasm, microthrombosis, neuronal apoptosis, and microglial activation. Additionally, human plasma and cerebrospinal fluid (CSF) samples from patients with SAH with and without vasospasm were evaluated for BVR-A expression and oxidative modifications using immunoprecipitation and western blot techniques.
    RESULTS: BV injection in the murine model induced significant vasospasm, increased microthrombosis, neuronal apoptosis, and a reactive morphological shift in microglia. In human samples, oxidative modifications of BVR-A were significantly raised in plasma from patients with SAH with vasospasm compared with those without, despite similar BVR-A expression levels. No significant differences in oxidative modifications were observed in CSF samples.
    CONCLUSION: This study shows a novel role of BV in vasospasm development and identifies oxidative modifications of BVR-A as potential modulators of SAH pathology. These findings suggest that BV and altered BVR-A activity may serve as biomarkers or therapeutic targets for improving outcomes in patients with SAH.
    Keywords:  Aneurysm; Cerebral Vasospasm; Subarachnoid Hemorrhage; biliverdin
    DOI:  https://doi.org/10.1136/jnis-2025-023108
  83. Front Cell Infect Microbiol. 2025 ;15 1580958
    Japanese encephalitis virus-associated human microglia induce cell death of human microvascular endothelial cells in receptor-independent infection.
    Isabelle Fellay, Pauline Blanc, Alexey Larionov, Léa Schlunke, Luis Filgueira, Nils Lannes.
       Introduction: The neurotropic virus Japanese encephalitis virus invades the human central nervous system, inducing neuroinflammation and further disruption of the blood-brain barrier. JEV interacts with various cell types of the blood-brain barrier including the endothelial cells. The present work aims to investigate impact of receptor-dependent and independent infection of human microvascular endothelial cells by Japanese encephalitis virus.
    Methods: Receptor-dependent infection was achieved using cell-free virus while receptor-independent infection was by co-culture of microvascular endothelial cells with virus-associated microglia.
    Results: While both receptor-dependent and independent infections of human microvascular endothelial cells led to virus propagation, only receptor-independent infection induced cell death of human microvascular endothelial cells. While the CX3CR1-CX3CL1 axis was inefficient in blocking virus rescue and protecting endothelial cell from cell death, transcriptomics analysis identified Tumour Necrosis Factor-related apoptosis inducing ligand and receptors as potential key player leading to endothelial cell death.
    Discussion: Overall, our findings demonstrate that human microvascular endothelial cells supply virus propagation and Japanese encephalitis virus-associated microglia greatly contribute to endothelial cell death, an important component of the blood brain barrier integrity. Importantly, Tumour Necrosis Factor-related apoptosis inducing ligand and receptors represents a promising therapeutic target preventing microvascular endothelial cell death after neuroinvasion.
    Keywords:  Japanese encephalitis (JE) virus; TRAIL (TNF-related apoptosis-inducing ligand); cytotoxicity; human microglia; intercellular interactions; microvascular endothelial cells; receptor-independent infection
    DOI:  https://doi.org/10.3389/fcimb.2025.1580958
  84. Lab Invest. 2025 May 21. pii: S0023-6837(25)00107-2. [Epub ahead of print] 104197
    Aryl hydrocarbon receptor deficiency upregulates intercellular adhesion molecule 1 in retinal pigment epithelial cells and contributes to retinal inflammation.
    Tsung-Min Yang, Te-Chao Fang, Yu-Cheng Lee, Chen-Chen Lee, Yen-Ju Chan, Ida Fitriana, Yu-Wen Cheng, Ching-Hao Li.
      Retinal pigment epithelium (RPE) cells, located between the photoreceptors and choroid, play a crucial role in maintaining retinal health and function. They act as immunosuppressive barriers, preventing immune cell infiltration from the choroid. Retinal inflammation contributes to the development of various ocular diseases. The aryl hydrocarbon receptor (AHR) is a well-established ligand-dependent transcription factor that mediates potent anti-inflammatory signals following ligand binding. AHR expression is notably reduced under several conditions that negatively affect the retina. We hypothesized that AHR protein loss may impairs RPE cell function, shifting them toward a pro-inflammatory phenotype. In this study, we investigated the pro-inflammatory pathways activated by AHR knockout (AHR-KO) and examined associated retinal phenotypic changes in AHR-KO mice. Our findings suggest that AHR deficiency may enhance the activity of αvβ3-integrin, extracellular signal-regulated kinases (ERK1/2), and p65 subunit of nuclear factor kappa B (NF-κB), leading to an upregulation of intercellular adhesion molecule 1 (ICAM1) and promoting monocyte adhesion in vitro. Introducing an AHR-green fluorescent protein into AHR-KO RPE cells or pre-treating the cells with pharmacological inhibitors targeting αvβ3 (cycloRGDfk), focal adhesion kinase (PF573228), phospholipase C (U73122), ERK1/2 (U0126), and NF-κB (Bay11-7082) prevented ICAM1 induction in AHR-KO RPE cells. These results suggest that the pro-inflammatory pathway is driven by AHR deficiency. In AHR-KO mice, retinal tissues showed ICAM1 accumulation, microglial activation, and migration, indicating chronic retinal inflammation due to AHR deficiency. These mice also displayed early-onset electroretinogram degeneration. Collectively, our data support the protective role of AHR in maintaining RPE cell physiology and retinal health.
    Keywords:  aryl hydrocarbon receptor; intercellular adhesion molecule 1; retinal inflammation; retinal pigment epithelium; αvβ3-integrin
    DOI:  https://doi.org/10.1016/j.labinv.2025.104197
  85. ACS Appl Mater Interfaces. 2025 May 22.
    Tannic Acid-Based Injectable Hydrogel Promotes the Recovery of Traumatic Brain Injury by Anti-Ferroptosis.
    Jing Xu, Danyi Shen, Yao Wang, Xingyue Han, Xinning Dong, Xin Chen, Haifeng Shu, Jianwen Hou, Sixun Yu.
      Traumatic brain injury (TBI) can trigger a series of complex physiological responses, with iron overload and neuronal ferroptosis playing particularly pivotal roles. These processes exacerbate secondary brain injury and significantly deteriorate neurological function. To address this challenge, this study developed an innovative local drug delivery strategy: an injectable, post-traumatic microenvironment-responsive hydrogel. The hydrogel, composed of tannic acid (TA) and quaternized chitosan (QCS), is designed to alleviate neurological deficits secondary brain injury following TBI through its anti-ferroptosis mechanism. In vitro, a ferroptosis model was established using HT22 cells treated with the ferroptosis inducer RSL-3, demonstrating the hydrogel's antioxidant capacity in the TBI-like conditions. The results showed that the hydrogel significantly restored cell viability, reversed iron accumulation, alleviated lipid peroxidation, and restored mitochondrial function. Further in vivo experiments in the TBI model showed that the TA/QCS hydrogel not only effectively inhibited neuronal degeneration, reduced iron accumulation, and lipid peroxidation but also restored mitochondrial function in neurons. Additionally, the hydrogel significantly attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes, thereby facilitating neurological recovery after TBI. This study offers novel insights into TBI management strategies aimed at preventing the progression of a secondary injury.
    Keywords:  ferroptosis; hydrogel; tannic acid; traumatic brain injury
    DOI:  https://doi.org/10.1021/acsami.5c02580
  86. Biol Direct. 2025 May 21. 20(1): 61
    Mechanism of LINC01018/miR-182-5p/Rab27B in the immune escape through PD-L1-mediated CD8+ T cell suppression in glioma.
    Su Hu, Guoshuo Chen, Aiping Luo, Hailin Zhao, Dan Li, Biao Peng, Jike Du, Dongdong Luo.
       BACKGROUND: Glioma is a malignant tumor associated with poorer prognosis. This study aims to elucidate the mechanism of LINC01018/miR-182-5p/Rab27B axis in PD-L1-mediated CD8+ T cell suppression in the progression of gliomas.
    METHODS: LINC01018, miR-182-5p, and Rab27B expression levels in glioblastoma tissues were measured. The proportion of infiltrating macrophages and monocytes and CD8+ T cell function were assessed. The relationship between miR-182-5p and Rab27B was analyzed. Glioma cell activity, invasion, and migration were measured. The expression of E-cadherin, N-cadherin, Vimentin, PD-L1, iNOS, and CD206 was determined. Glioma cell-derived EVs were isolated, and the co-localization of Rab27B and PD-L1 and the binding of Rab27B to PD-L1 were analyzed. The endocytosis of EVs by microglia was assayed. The impact of LINC01018/miR-182-5p/Rab27B on glioma growth was observed. The function of macrophages and CD8+ T cells in tumors was analyzed.
    RESULTS: Rab27B was downregulated, and infiltrating macrophages and monocytes were increased in glioblastoma. miR-182-5p inhibited Rab27B expression. Rab27B knockdown reverses the inhibitory effect of LINC01018 overexpression on glioma cell growth. Glioma cells-derived EVs with low Rab27B expression carried more PD-L1 to increase PD-L1 expression and M2 polarization in microglia. LINC01018 overexpression reduced macrophages in orthotopic tumors. CD8+ T cell numbers showed no significant difference, but TIM-3 increased and IFN-γ decreased. miR-182-5p inhibition enhanced the therapeutic effect of anti-PD-L1, which was reversed after glioma cell-derived EVs.
    CONCLUSION: LINC01018 promotes PD-L1-mediated CD8+ T cell suppression via the miR-182-5p/Rab27B axis in glioma cell-derived EVs, thereby contributing to immune escape in gliomas.
    Keywords:  EVs; Glioma; Immune escape; LINC01018; Rab27B; miR-182-5p
    DOI:  https://doi.org/10.1186/s13062-025-00651-w
  87. Small. 2025 May 19. e2412170
    Engineered Exosome-Loaded Silk Fibroin Composite Hydrogels Promote Tissue Repair in Spinal Cord Injury Via Immune Checkpoint Blockade.
    Xiaoyu Dong, Yang Lu, Qianqian Hu, Chenzi Zeng, Jiaxiao Zheng, Jiayi Huang, Haoru Dong, Peng Zou, Tianyu Wang, Yueqi Wu, Jiaqin Shao, Kailiang Zhou, Guangheng Xiang, Jian Xiao.
      Spinal cord injury (SCI) is a severe central nervous system disorder characterized by a high rate of disability and limited axonal regeneration. Excessive post-injury inflammation often leads to further neuronal damage. Immune checkpoint (IC) genes, which regulate immune cell activity, play a critical role in modulating post-injury inflammation and thus influence neural repair and functional recovery. In this study, analysis of the GEO database reveals that the IC gene T cell immunoglobulin and mucin domain-containing protein 3 (Tim3) is highly expressed in microglia following SCI, contributing to an exacerbated inflammatory response. To address this, an RNAi-Tim3-Exo@SF hydrogel system is designed to deliver siRNA-Tim3 via exosomes, thereby regulating Tim3 expression after injury. Furthermore, miRNA sequencing indicates that the engineered exosomes (RNAi-Tim3-Exo) encapsulated within the hydrogel have the potential to promote axonal regeneration and modulate the spinal cord microenvironment. Preclinical studies demonstrate that the RNAi-Tim3-Exo@SF hydrogel could stabilize microtubules, promote damaged axon regeneration, stimulate angiogenesis, modulate the inflammatory environment, and ultimately improve motor function in SCI mouse models. Mechanistically, these reparative effects may be associated with miR-155-5p contained within the RNAi-Tim3-Exo. By integrating bioinformatics, biomedical science, and tissue engineering, this study presents a novel hydrogel-based therapeutic strategy with significant potential for the treatment of SCI.
    Keywords:  engineered exosomes; hydrogels; immune checkpoint blockade; spinal cord injury
    DOI:  https://doi.org/10.1002/smll.202412170
  88. Lancet Neurol. 2025 Jun;pii: S1474-4422(25)00116-4. [Epub ahead of print]24(6): 524-534
    Protective genetic variants against Alzheimer's disease.
    Claudia Marino, Vincent Malotaux, Averi Giudicessi, David Aguillon, Diego Sepulveda-Falla, Francisco Lopera, Yakeel T Quiroz.
      Genetic studies can offer powerful insights for the development of disease-modifying therapies for Alzheimer's disease. Protective genetic variants that delay the onset of cognitive impairment have been found in people with sporadic Alzheimer's disease and in carriers of mutations that usually cause autosomal-dominant Alzheimer's disease in mid-life. The study of families who carry autosomal dominant mutations provides a unique opportunity to uncover genetic modifiers of disease progression, including rare variants in genes such as APOE and RELN. Understanding how these variants confer protection can help identify the biological pathways that contribute to cognitive resilience, such as the heparan-sulphate proteoglycan-APOE receptor pathway, the TREM-2-driven signalling pathways in the microglia, and phagocytosis. Therapies able to replicate the beneficial effects of these natural defences could provide novel strategies for slowing or preventing the progression of Alzheimer's disease.
    DOI:  https://doi.org/10.1016/S1474-4422(25)00116-4
  89. J Biochem Mol Toxicol. 2025 Jun;39(6): e70295
    Hypericin Regulates Inflammation Levels and Improves Depressive Symptoms in Rats With Post-Stroke Depression Through the MEK/ERK/CREB Pathway.
    Kui Jia, Wenlong Li, Yifan Li, Lingling Qian.
       OBJECTIVE: To investigate the effect of hypericin on ameliorating depressive behaviour in post-stroke depression (PSD) rats.
    METHODS: Rats underwent a middle cerebral artery occlusion and chronic mild stress for 28 days to create a PSD model. Behavioural tests included the open field test (OFT) and the elevated plus maze test. Hypericin at a low (100 mg/kg) and a high (400 mg/kg) dose was administered via gavage. Lipopolysaccharide (LPS) was used to establish a microglia-injury model, with hypericin treatment at 0.25, 0.5, 1, and 2 μmol/L, and ELISA was used to measure serotonin (5-HT), interleukin (IL)-6 and IL-10 levels. Additionally, Western blot analysis and immunohistochemistry analysed protein levels and the expression of iNOS and Arg-1 in the hippocampus.
    RESULTS: Following the PSD model preparation, the rats showed substantially reduced movement in the OFT and spent less time in the open arms of the elevated plus maze, whereas treatment with hypericin and fluoxetine improved depressive behaviour in these tests. In addition, hypericin decreased IL-6, increased IL-10 and 5-HT and enhanced p-MEK/MEK, p-ERK/ERK and p-CREB/CREB expression in the serum of the PSD rats and the LPS cell model. Hypericin also reduced iNOS but increased Arg-1 expression in the PSD rat hippocampus.
    CONCLUSION: Hypericin promotes M2 microglial polarisation, reduces inflammation and improves depressive behaviour in PSD rats by activating the MEK/ERK/CREB pathway.
    Keywords:  MEK/ERK/CREB pathway; hypericin; inflammatory factors; microglia; post‐stroke depression
    DOI:  https://doi.org/10.1002/jbt.70295
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