bims-microg 2025-09-07 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–09–07
thirty papers selected by
Marcus Karlstetter, Universität zu Köln

Rhapontigenin attenuates neurodegeneration in a parkinson's disease model by downregulating mtDNA-cGAS-STING-NF-κB-mediated neuroinflammation via PINK1/DRP1-dependent microglial mitophagy.
Knockout of P2Y12 receptor facilitates neuronal envelopment by reactive microglia and accelerates prion disease.
Neonatal microglia replacement in mice modulates seizure severity in adulthood.
Dual Pro-Angiogenic and Pro-Fibrotic MARCO+ Microglial Phenotype in Diabetic Retinopathy.
The human microglia responsome: a resource for microglia states in health and disease.
NLRP6 governs hippocampal microglial phagocytosis to resist stress-induced depressive-like behaviors in mice and the intervention effect of bezafibrate.
Palmatine mitigates ischemic brain injury by regulating microglial polarization and sphingolipid metabolism.
Intraoperative application of an antioxidant nanoparticle-hydrogel targeting microglia regulates neuroinflammation in traumatic brain injury.
C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.
Human microglia reduce alpha-synuclein aggregation and are neuroprotective in adult mouse brain.
RHBDF2 governs microglial neuroinflammation during cerebral ischemia-reperfusion injury and is positively regulated by the m6A reader YTHDF1.
Targeting phagocytosis for amyloid-β clearance: implications of morphology remodeling and microglia activation probed by bifunctional chimaeras.
ADAM17 Inhibition Protects Cognition in Intermittent Hypoxia: The Role of TREM2.
Electroacupuncture Pretreatment Alleviates Myocardial Ischemia-Reperfusion Injury by Inhibiting Engulfment by Microglia in the Lateral Hypothalamus.
TREM2 mediates parkinsonism-like neurodegeneration in carbon disulfide-induced neurotoxicity.
PICALM Alzheimer's risk allele causes aberrant lipid droplets in microglia.
β-Carotene Suppresses Lipopolysaccharide-induced Nitric Oxide Production in Microglia via Retinoic Acid Receptor-dependent Mechanisms.
Buyang Huanwu Decoction Promotes Post-Stroke White Matter Repair via TREM2-Dependent Microglial Phagocytosis and IGF1 Secretion.
MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer's disease model.
Defective Hoxb8 microglia are causative for both chronic anxiety and pathological overgrooming in mice.
Cytoskeletal control in adult microglia is essential to restore neurodevelopmental synaptic and cognitive deficits.
Microglia-derived exosomes modulate myelin regeneration via activating Nrf2 signaling pathway in oligodendrocyte precursor cells in MS.
Hypoxic stress dysregulates functions of glioma-associated myeloid cells through epigenomic and transcriptional programs.
Microglial-derived nitric oxide regulates amygdala synaptic plasticity to drive chronic pain and depression induced by lumbar disc herniation.
Nanoparticles Induce Protein Corona Conformational Change to Reshape Intracellular Interactome for Microglial Polarization.
SARS-CoV-2 vaccination during pregnancy enhances offspring hippocampal neurogenesis and working memory via IFN-γ-responsive microglia.
β-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity.
A rare intronic c.2654+1G>A mutation in CSF1R-microglial encephalopathy: a case report.
Melatonin alleviates retinal damage and visual function impairment by suppressing ROS/TXNIP/NLRP3 signalling and inhibiting microglial activation in rats with optic nerve crush injury.
P2X7-CaMKII drives 5-LOX nuclear translocation to impair microglial function after subarachnoid hemorrhage.

Cell Mol Life Sci. 2025 Sep 06. 82(1): 337

Rhapontigenin attenuates neurodegeneration in a parkinson's disease model by downregulating mtDNA-cGAS-STING-NF-κB-mediated neuroinflammation via PINK1/DRP1-dependent microglial mitophagy.

Zhongqiang Su, Hui Shu, Xingting Huang, Liuyan Ding, Fengchu Liang, Zongtang Xu, Ziting Zhu, Minshan Chen, Xiaobei Wang, Guihua Li, Huan Xia, Qiannan Cao, Wenlong Zhang, Pingyi Xu, Xinling Yang.

  Microglial activation-induced neuroinflammation and impaired neuronal mitophagy are recognized as pivotal pathogeneses in Parkinson's disease (PD). However, the role of microglial mitophagy in microglial activation during PD development remains unclear, and therapeutic interventions targeting this interaction are lacking. Rhapontigenin (Rhap), a stilbenoid enriched in Vitis vinifera, exhibits dual anti-neuroinflammatory and mitophagy-enhancing properties, but its therapeutic potential and mechanisms in PD are unexplored. This study aimed to investigate the therapeutic efficacy of Rhap on neurodegeneration in a PD model and explore its underlying mechanism. Here, we showed that Rhap administration significantly ameliorated motor deficits, dopaminergic neuron loss, and neuroinflammation in MPTP-induced PD mice. Mechanistically, Rhap suppressed neuroinflammation by inhibiting the cGAS-STING-NF-κB signaling axis in both PD model mice and MPP⁺-induced BV2 microglia. Crucially, its anti-inflammatory effects depend on the PINK1-mediated enhancement of microglial mitophagy to control cytosolic mtDNA leakage. Specifically, Rhap bound to PINK1 strengthened the PINK1-DRP1 interaction, promoted mitochondrial fission in damaged organelles, and enhanced mitophagy clearance. This mitophagy activation prevents cytosolic leakage of mitochondrial DNA (mtDNA), thereby attenuating mtDNA-cGAS-STING-NF-κB-derived neuroinflammation and subsequent neurodegeneration in PD. PINK1 deficiency in BV2 microglia abolished Rhap's ability to suppress mtDNA-cGAS-STING-NF-κB activation and enhance mitophagy. Overall, our study reveals a previously unrecognized mechanism by which Rhap ameliorates PD-associated neurodegeneration through dual modulation of PINK1/DRP1-dependent microglial mitophagy and the mtDNA-cGAS-STING-NF-κB neuroinflammatory axis, suggesting a potential therapeutic strategy for PD and related neurodegenerative disorders.

Keywords:  CGAS-STING; Microglial mitophagy; Mitochondrial DNA; Neuroinflammation; Parkinson's disease; Rhapontigenin

DOI:  https://doi.org/10.1007/s00018-025-05873-9
J Neuroinflammation. 2025 Aug 31. 22(1): 210

Knockout of P2Y12 receptor facilitates neuronal envelopment by reactive microglia and accelerates prion disease.

Natallia Makarava, Tarek Safadi, Olga Bocharova, Olga Mychko, Narayan P Pandit, Kara Molesworth, Ukpong B Eyo, Ilia V Baskakov.

   BACKGROUND: Microglia continuously monitor neuronal health through somatic purinergic junctions, where microglial processes establish dynamic contacts with neuronal cell bodies. The P2Y12 receptor is a key component of these junctions, essential for intercellular communication between ramified microglia and neurons under homeostatic conditions. However, during chronic neurodegeneration, such as that seen in prion diseases, microglia transition from process-based surveillance to extensive body-to-body interactions, enveloping neuronal somata. Despite its widespread use as a homeostatic marker, the functional role of P2Y12 in chronic neurodegenerative contexts remains largely unexplored.
METHODS: We investigated how genetic deletion of P2Y12 affects microglial morphology and microglia-neuron interactions in both healthy and prion-infected adult mice. In parallel, we assessed the impact of P2Y12 loss on prion disease progression and associated neuropathology.
RESULTS: In healthy adult mice, deletion of P2Y12 significantly disrupted canonical process-to-soma contacts, while paradoxically promoting increased microglia-neuron body-to-body interactions. This finding uncovers a previously unrecognized, P2Y12-independent mode of microglial engagement with neurons. Strikingly, in prion-infected mice, P2Y12 loss significantly increased the prevalence of neuronal envelopment by reactive microglia, and accelerated disease progression. Notably, this acceleration occurred without affecting prion accumulation or hippocampal neuronal loss, implicating altered microglia-neuron interactions - specifically excessive envelopment - as a key driver of disease exacerbation.
CONCLUSIONS: This study redefines P2Y12 not as a passive marker of homeostasis but as an active regulator of neuroimmune dynamics. We demonstrate that P2Y12 is essential for maintaining balanced microglia-neuron communication under physiological conditions and for restraining maladaptive microglial behavior during chronic neurodegeneration associated with prion disease. These findings uncover a novel mechanism by which microglia contribute to disease progression and position P2Y12 as a potential therapeutic target for modulating microglial responses in neurodegenerative disorders.

Keywords:  Microglia-neuron interactions; microglia mobility; Neurodegenerative diseases; P2Y12 receptor; Prion diseases; Prions; Reactive microglia

DOI:  https://doi.org/10.1186/s12974-025-03542-z
Mol Ther. 2025 Aug 26. pii: S1525-0016(25)00669-0. [Epub ahead of print]

Neonatal microglia replacement in mice modulates seizure severity in adulthood.

Carleigh A O'Brien, Samuelle A S Delcy, Sangeeta Shukla, Eli M Levitt, Akiva S Cohen, Mariko L Bennett, Frederick C Bennett.

Microglia replacement therapy, where endogenous brain macrophages are depleted and replaced by adoptively transferred surrogates, holds promise for treating pediatric neurologic diseases, but little is known about how early life microglia replacement impacts the brain. We sought to investigate how early postnatal microglia depletion and adoptive macrophage transfer, essential components of microglia replacement, durably impact neural circuits in a mouse model. Using both pharmacologic and genetic models, postnatal microglia depletion worsened adult seizure severity, mortality and neuropathology in a chemical seizure model. Replacement of endogenous microglia by adoptive transfer of monocytes rescued this effect, while transfer of authentic microglia from a donor mouse did not, and even worsened seizure phenotypes. RNA sequencing of transplanted microglia, monocyte-derived surrogates, and endogenous microglia revealed distinct state changes across groups in response to chemically induced seizure, demonstrating that both ontogeny and adoptive transfer significantly impact resident macrophage responses to the excitotoxic brain environment. In sum, we established models for neonatal microglia depletion and replacement, then applied them to identify durable impacts of depletion and reconstitution on the brain environment. We ultimately identified differential responses of macrophages to excitotoxic challenge based on their ontogeny, underscoring focus areas for ongoing preclinical development of microglia replacement therapies.

DOI: https://doi.org/10.1016/j.ymthe.2025.08.039
FASEB J. 2025 Sep 15. 39(17): e71006

Dual Pro-Angiogenic and Pro-Fibrotic MARCO+ Microglial Phenotype in Diabetic Retinopathy.

Qinyuan Gu, Xiying Mao, Jingyi Xu, Pengfei Ge, Xinjing Wu, Chengkun Wang, Jingfan Wang, Hongying Li, Yuanyuan Fan, Tianhao Xiao, Qinghuai Liu, Ping Xie, Zizhong Hu.

  Proliferative diabetic retinopathy (PDR) is a complication of diabetic microangiopathy that can cause severe visual impairment. Due to retinal neovascularization and fibrovascular membrane (FVM) formation, inhibition of vascularization and fibrosis plays a key role in PDR. In our study, single-cell sequencing of FVMs from PDR patients identified a MARCO+ microglial subpopulation exhibiting both pro-angiogenic and pro-fibrotic effects. In vitro experiments demonstrated that glycated albumin (GA) significantly upregulated MARCO expression in BV2 cells in a dose-dependent manner. In vivo experiments, oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models were established in wild-type (WT) and MARCO-/- mice. The accumulation of MARCO+ microglia promoted retinal angiogenesis and fibrogenesis in WT mouse models, but not in MARCO-/- mouse models. Mechanistically, next-generation sequencing confirmed that the activation of the TLR4/NF-κB signaling pathway results in the increased expression of MARCO+ microglia. Furthermore, the targeted drug PolyG, which inhibits MARCO+ microglia, resulted in reduced angiogenesis and fibrogenesis in mouse models. Taken together, we demonstrate that MARCO+ microglia could be a potential therapeutic target for ocular angiogenic and fibrotic diseases.

Keywords:  MARCO protein; diabetic retinopathy; fibrosis; microglia; neovascularization

DOI:  https://doi.org/10.1096/fj.202502138R
Brain Behav Immun. 2025 Sep 01. pii: S0889-1591(25)00330-7. [Epub ahead of print] 106095

The human microglia responsome: a resource for microglia states in health and disease.

Gijsje J L J Snijders, Katia de Paiva Lopes, Marjolein A M Sneeboer, Benjamin Z Muller, Frederieke A J Gigase, Dante D'Urso, Ricardo A Vialle, Roy Missall, Raphael Kubler, Towfique Raj, Jack Humphrey, Lot D de Witte.

  Microglia, the immune cells of the brain, are increasingly implicated in neurodegenerative disorders through genetic studies. However, how genetic risk factors for these diseases are related to microglial gene expression, microglial function, and ultimately disease, is still largely unknown. Microglia change rapidly in response to alterations in their cellular environment, which is regulated through changes in transcriptional programs, which are yet poorly understood. Here, we compared the effects of a set of inflammatory and restorative stimuli (lipopolysaccharide, interferon-gamma, resiquimod, tumor necrosis factor-alpha, adenosine triphosphate, dexamethasone, and interleukin-4) on human enriched microglial cells from 67 different donors (N = 398 samples, primarily aged >60 years) at the gene and transcript level. We show that enriched microglia from different anatomical brain regions show distinct responses to inflammatory stimuli. We define specific enriched microglial signatures across conditions which are highly relevant for a wide range of biological functions and complex human diseases. Finally, we used our stimulation signatures to interpret associations from Alzheimer's disease (AD) (genetic) studies and enriched microglia. Together, we provide a comprehensive transcriptomic resource of the human microglia responsome.

Keywords:  Disease; Inflammatory triggers; Microglia

DOI:  https://doi.org/10.1016/j.bbi.2025.106095
J Adv Res. 2025 Aug 26. pii: S2090-1232(25)00666-6. [Epub ahead of print]

NLRP6 governs hippocampal microglial phagocytosis to resist stress-induced depressive-like behaviors in mice and the intervention effect of bezafibrate.

Fan Yang, Xiuqin Kong, Yuefeng Hu, Wanzhao Liu, Pengfei Xie, Yuexi Gu, Yan Zhang, Yili Yang, Chuanfeng Tang, Jianmei Li.

   INTRODUCTION: Microglial phagocytosis is crucial for maintaining central nervous system (CNS) homeostasis and is implicated in the development of depression. NOD-like receptor family pyrin domain containing 6 (NLRP6) represents a potential target for depression treatment, but underlying mechanisms remain unclear. Bezafibrate has been shown to exhibit multiple neuroprotective effects.
OBJECTIVES: To investigate the effects of NLRP6 on microglial phagocytosis and depressive-like behaviors, elucidate the potential underlying mechanisms, and evaluate bezafibrate's therapeutic impact.
METHODS: NLRP6 complete gene knockout (Nlrp6-KO), microglia-conditional knockout (Nlrp6-cKO), and chronic restraint stress (CRS) model were established in mice. Behavioral tests (OFT, TST, FST, SPT) were used to assess depressive-like behaviors. Fluorescently labeled cellular debris was stereotactically injected into the hippocampus or co-cultured with the BV2 microglial cell line to assess the microglial phagocytic activity. Underlying mechanisms were investigated using RNA-seq, luciferase assays, flow cytometry, Western blot, qPCR, and ELISA.
RESULTS: Enriched NLRP6 expression in microglia was confirmed by RNAscope experiment. Nlrp6-KO and Nlrp6-cKO mice exhibited significant depressive-like behaviors, accompanied by impaired microglial phagocytic function. In the BV2 cells, NLRP6 regulated phagocytosis of cellular debris by promoting the transactivation of cluster differentiation 36 (CD36). More importantly, corticosterone inhibited NLRP6 and its target gene CD36 expression, thereby reducing microglial phagocytosis. However, bezafibrate treatment restored the NLRP6-CD36 axis, enhanced microglial phagocytosis, and suppressed the inflammatory response to cellular debris in BV2 cells. In CRS mice, bezafibrate alleviated depressive-like behaviors, reversed NLRP6/CD36 downregulation, improved phagocytosis, and reduced hippocampal neuroinflammation. Importantly, bezafibrate failed to alleviate depressive-like behaviors in Nlrp6-KO mice, indicating NLRP6 is essential for its antidepressant effect.
CONCLUSION: NLRP6 critically regulates microglial phagocytosis via CD36, combating depression. Bezafibrate alleviates stress-induced depressive behaviors and neuroinflammation primarily by enhancing NLRP6-dependent phagocytosis. Thus, NLRP6 represents a promising therapeutic target in hippocampal microglia for maintaining CNS homeostasis and treating depression.

Keywords:  Bezafibrate; CD36; Microglia; NLRP6; Phagocytosis

DOI:  https://doi.org/10.1016/j.jare.2025.08.050
Int Immunopharmacol. 2025 Sep 04. pii: S1567-5769(25)01435-3. [Epub ahead of print]165 115444

Palmatine mitigates ischemic brain injury by regulating microglial polarization and sphingolipid metabolism.

Ningjing Wang, Xiaotong Wei, Peng Zhou, Weizhen Wu, Jiarui Liu, Huaxu Zhu, Zhishu Tang, Xin Chai, Nianyun Yang, Qingyu Zhang, Yinfeng Dong, Rui Guo, Qichun Zhang.

   BACKGROUND: To elucidate the therapeutic effects and underlying mechanisms of palmatine, a principal alkaloid derived from Coptis chinensis, on neuroinflammation in ischemic stroke rat models induced by middle cerebral artery occlusion (MCAO).
METHODS: Initially, qPCR was employed to assess the impact of neurotrophic factors secreted by SH-SY5Y neuroblastoma cells on the phenotypes of BV2 cells. Alterations in sphingolipid profiles within neuronal supernatants were characterized using liquid chromatography-tandem mass spectrometry, and molecular docking studies were conducted to investigate the interaction of palmatine with key enzymes involved in sphingolipid metabolism. Subsequently, Rats were subjected to MCAO to mimic cerebral ischemia in vivo. Neurological function was evaluated using standardized tests, and brain pathology was assessed. LC-MS/MS was also utilized to quantify sphingolipid levels within the brain. BV2 cells and rats were subjected to TREM2 knockdown using lentiviral transfection and adeno-associated virus (AAV)-mediated delivery, respectively. The neuroprotective effects of palmatine were further delineated.
RESULTS: In vitro, palmatine counteracted ischemia-induced microglial M1 polarization, promoting a neuroprotective M2 phenotype in BV2 cells. It modulated sphingolipid metabolism, normalizing ceramide and ceramide-1-phosphate levels in neuronal supernatants. In vivo, palmatine significantly ameliorated neurological deficits and restored sphingolipid homeostasis in MCAO-induced rats. TREM2 downregulation exacerbated ischemic injury, whereas SH-SY5Y-derived neurotrophic factors suppressed BV2 activation. Inhibition of the PI3K/AKT/mTOR/HIF-1α signaling cascade significantly attenuated palmatine's microglia-mediated neuroprotection.
CONCLUSION: Palmatine exerts neuroprotection by reducing levels of ceramide through its conversion to ceramide-1-phosphate, a process that is mediated by TREM2 on microglia and the PI3K/AKT/mTOR/HIF-1α signaling pathway.

Keywords:  Cerebral ischemia; Microglia; Neuroinflammation; Palmatine; Sphingolipid metabolism; TREM2

DOI:  https://doi.org/10.1016/j.intimp.2025.115444
J Nanobiotechnology. 2025 Sep 01. 23(1): 599

Intraoperative application of an antioxidant nanoparticle-hydrogel targeting microglia regulates neuroinflammation in traumatic brain injury.

Yuhan Han, Jiacheng Gu, Miaomiao Xu, Yufei Ma, Weiji Weng, Qiyuan Feng, Zhenghui He, Wenlan Qi, Qing Mao, Jiyao Jiang, Junfeng Feng.

  Microglia play a critical role in neuroinflammation, a key secondary injury mechanism following traumatic brain injury (TBI). The colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 has shown promise in suppressing neuroinflammation by depleting microglia, but it lacks specificity in targeting microglia at the injury site. To overcome this limitation, we developed PLX5622 nanoparticles functionalized with the CAQK peptide for lesion-specific targeting and combined them with a hydrogel (GelMA-PPS) that possesses potent reactive oxygen species (ROS) scavenging capabilities. This nanoparticle-hydrogel drug delivery system (GelMA-PPS/P) significantly enhanced the delivery efficiency and therapeutic efficacy of PLX5622 in TBI treatment. Localized administration of this system effectively depleted microglia at the injury site, suppressed neuroinflammation, and reduced the release of inflammatory cytokines. Its ROS scavenging ability was also validated in vitro and in vivo. Together, these effects synergistically improved neurological function recovery in TBI mouse models. This innovative strategy offers a comprehensive and targeted approach to managing neuroinflammation after TBI, providing a promising avenue for advancing TBI therapies.

Keywords:  Microglia; Nanoparticle-hydrogel; Neuroinflammation; ROS scavenging; Traumatic brain injury

DOI:  https://doi.org/10.1186/s12951-025-03682-7
Glia. 2025 Sep 01.

C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.

Marika Mearelli, Insa Hirschberg, Christin Weissleder, Carmela Giachino, María José Pérez, Malvina Dubroux, Francesca Provenzano, Mafalda Rizzuti, Linda Ottoboni, Udit Sheth, Tania F Gendron, Stefania Corti, Michela Deleidi.

  The C9orf72 hexanucleotide repeat expansion mutation is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but its cell type-specific effects on energy metabolism and immune pathways remain poorly understood. Using induced pluripotent stem cell (iPSC)-derived motor neurons, astrocytes, and microglia from C9orf72 patients and their isogenic controls, we investigated metabolic changes at the single-cell level under basal and inflammatory conditions. Our results showed that microglia are particularly susceptible to metabolic disturbances. While C9orf72 motor neurons exhibited impaired mitochondrial respiration and reduced ATP production, C9orf72 microglia presented pronounced increases in glycolytic activity and oxidative stress, accompanied by the upregulation of the expression of key metabolic enzymes. These metabolic changes in microglia were exacerbated by inflammatory stimuli. To investigate how these changes affect the broader cellular environment, we developed a human iPSC-derived triculture system comprising motor neurons, astrocytes, and microglia. This model revealed increased metabolic activity in all cell types and highlighted that microglia-driven metabolic reprogramming in astrocytes contributes to the vulnerability of motor neurons under inflammatory conditions. Our findings highlight the central role of microglia in driving metabolic dysregulation and intercellular crosstalk in ALS pathogenesis and suggest that targeting metabolic pathways in immune cells may provide new therapeutic avenues.

Keywords:   C9orf72 ; amyotrophic lateral sclerosis/frontotemporal dementia; glial‐neuronal communication; immune system; induced pluripotent stem cells; microglia

DOI:  https://doi.org/10.1002/glia.70080
Brain Behav Immun. 2025 Sep 03. pii: S0889-1591(25)00332-0. [Epub ahead of print] 106097

Human microglia reduce alpha-synuclein aggregation and are neuroprotective in adult mouse brain.

Katrina Albert, Sanni Peltonen, Anni Vanne, Sara Kälvälä, Valtteri Syvänen, Jari Koistinaho, Kelvin C Luk, Šárka Lehtonen.

  Microglia, brain-resident immune cells, are involved in pathophysiology of several neurodegenerative diseases, including Parkinson's disease. Given significant species-specific differences in microglia gene expression, particularly in disease-risk genes, as well as the highly reactive nature of these cells, studying human microglia in a whole brain environment is essential. Here, we established a humanized mouse model by transplanting human induced pluripotent stem cell-derived hematopoietic progenitor cells into the striatum of immunodeficient adult mice and injected human alpha-synuclein preformed fibrils to model Parkinson's disease pathology. Transplanted human cells engraft, mature into microglia and maintain their phenotype for at least three months post-transplantation. These human microglia interact with alpha-synuclein, significantly limiting its propagation from the striatum to the substantia nigra and further reducing local small aggregates; they also mildly protect tyrosine hydroxylase neurons there. Transcriptomic profiling reveals 56 differentially expressed genes in human microglia in response to alpha-synuclein preformed fibrils, while host mouse cells show 202 gene expression changes, including an upregulation of gene Hcrt (fold change = 7.77, p = 0.0015). Immunohistochemistry analysis further confirms the preservation of hypocretin-positive neurons in the hypothalamus of the transplanted mice (p = 0.0079). The findings highlight the neuroprotective role of human microglia and establish a more disease-relevant in vivo model for investigating alpha-synuclein aggregation and therapeutic interventions in Parkinson's disease.

Keywords:  Alpha-synuclein; Hypocretin; Microglia; Parkinson’s disease; Preformed fibrils; RNAseq; Xenotransplant

DOI:  https://doi.org/10.1016/j.bbi.2025.106097
Mol Med. 2025 Sep 02. 31(1): 284

RHBDF2 governs microglial neuroinflammation during cerebral ischemia-reperfusion injury and is positively regulated by the m6A reader YTHDF1.

Lisi Xu, Ruonan Zhang, Xiaolin Zhang, Bing Liu, Xiuli Shang, Daifa Huang.

   BACKGROUND: Neuroinflammation mediated by microglia activation is the key pathological mechanisms for cerebral ischemia-reperfusion injury (CIRI). This study investigated the role and underlying molecular mechanism of Rhomboid 5 homolog 2 (RHBDF2) in neuroinflammation during CIRI.
METHODS: The in vivo middle cerebral artery occlusion and reperfusion (MCAO/R) mouse model and in vitro HMC3 microglia subjected to oxygen glucose deprivation and reperfusion (OGD/R) were established to mimic CIRI. Real-time PCR, western blot, immunohistochemistry, immunofluorescence, flow cytometry, and co-immunoprecipitation assays were used to confirm RHBDF2 expression and explore the molecular mechanism of microglia-specific RHBDF2 knockdown in CIRI. Methylated RNA immunoprecipitation was used to detect the m6A methylation level of RHBDF2 mRNA both in vivo and in vitro. RNA sequencing analysis was performed in OGD/R-treated HMC3 cells with or without RHBDF2 knockdown.
RESULTS: Our finding showed that RHBDF2 expression increased in both in vivo and in vitro CIRI models. Microglial-specific RHBDF2 knockdown reduced brain injury in MCAO/R mice, as evidenced by the reduction in the cerebral infarct volume and amelioration of the neurological deficits. Furthermore, we demonstrated that RHBDF2 knockdown alleviated neuroinflammation by inhibiting microglial M1 polarization and promoting microglial M2 polarization in MCAO/R mouse ischemic penumbra. Mechanistically, RHBDF2 interacted with STING and promoted the activation of the STING-TBK1-IRF3/p65 signaling pathway. Rescue experiments confirmed that RHBDF2 knockdown suppressed inflammation via the inhibition of STING-TBK1 signaling pathway. In addition, the m6A methylation level of RHBDF2 mRNA was significantly increased in the MCAO/R mouse brain tissues and OGD/R-treated HMC3 cells. YTHDF1 recognized the m6A sites of RHBDF2 and promote its expression in an m6A manner. Through RNA-seq, the possible downstream effectors of RHBDF2 in CIRI was predicted.
CONCLUSIONS: Microglial-specific RHBDF2 knockdown inhibits neuroinflammation in CIRI via STING-TBK1 signaling pathway, and is positively regulated by the m6A reader YTHDF1. This suggests RHBDF2 as a potential therapeutic target in ischemic stroke.

Keywords:  Cerebral ischemia–reperfusion injury; Microglia; RHBDF2; RNA m6A methylation; STING

DOI:  https://doi.org/10.1186/s10020-025-01326-y
Nat Commun. 2025 Aug 30. 16(1): 8128

Targeting phagocytosis for amyloid-β clearance: implications of morphology remodeling and microglia activation probed by bifunctional chimaeras.

Youqiao Wang, Zeyi Wang, Ziyi Liu, Jinyan Li, Shuo Yang, Yuxuan Zhao, Yangmei Huang, Chenyang Liao, Yiqiu Zhang, Jiaojiao Zhao, Weilin Zhou, Binhua Zhou, Xin Yue, Qiang Zhou, Xianzhang Bu.

Amyloid-β (Aβ), a key driver of Alzheimer's disease (AD) pathogenesis, possesses diverse harmful and clearance-resistant structures that present substantial challenges to therapeutic development. Here, we demonstrate that modulating Aβ morphology, rather than Toll-like receptor 2 (TLR2)-dependent microglia activation, is essential for effective phagocytosis of Aβ species by microglia. By developing a bifunctional mechanistic probe (P2CSKn) designed to remodel Aβ and activate TLR2, we show it restructures soluble Aβ (sAβ) and fibrillar Aβ (fAβ) into less toxic hybrid aggregates (hPAβ). Critically, this structural remodeling protects microglia from Aβ toxicity while enabling robust phagocytosis. Moreover, although TLR2 activation mildly enhances Aβ uptake, it concurrently triggers detrimental inflammation that negates its benefits. Our findings establish morphological remodeling as the critical determinant of effective Aβ clearance and suggest a morphology-focused strategy for developing safe therapeutics for Aβ-related diseases.

DOI: https://doi.org/10.1038/s41467-025-63458-3
Nat Sci Sleep. 2025 ;17 1915-1928

ADAM17 Inhibition Protects Cognition in Intermittent Hypoxia: The Role of TREM2.

Jiahuan Xu, Hongyu Jin, Xiaomeng Li, Zhiping Jiang, Fanqi Meng, Wei Wang, Wen-Yang Li.

   Purpose: The triggering receptor expressed on myeloid cells 2 (TREM2) is a new therapeutic target in Alzheimer's disease. However, its role in obstructive sleep apnea (OSA)-related cognitive impairment is still unclear. This study aimed to investigate the effect and regulatory mechanism of TREM2 on cognitive impairment related to OSA.
Methods: Since intermittent hypoxia (IH) is the primary pathophysiologic characteristic of OSA, we conducted IH animal and BV2 cell model to investigate the mechanism. Trem2 knockdown and Trem2 overexpression cells were created by Lentivirus transfection. A disintegrin and metalloprotease 17 (ADAM17) is the primary enzyme for TREM2 shedding, we used TAPI-1 to inhibit its activity. Morris water maze, Nissl staining, real-time PCR, immunofluorescence, Western blotting, fluorometric assay kit, and enzyme-linked immunosorbent assay were used to explore the molecular mechanism.
Results: The TREM2 levels were decreased in BV2 cells exposed to IH for 24 hours. IH elevated the levels of IL-1β, TNF-α and CD86 in BV2 cells, as well as the levels of p-Tau in conditioned media-cultured HT-22 cells. Conversely, IH reduced the levels of IL-10 and CD206 in BV2 cells. However, these effects were exacerbated in BV2 cells with Trem2 knockdown, whereas they were mitigated in those with Trem2 overexpression. Additionally, the ADAM17 activity and soluble TREM2 (sTREM2) levels were increased in BV2 cells subjected to IH. Treatment with TAPI-1, suppressed ADAM17 activity and restored TREM2 expression both in vitro and in vivo. Inhibition of ADAM17 led to a reduction in the expression of CD86, IL-1β, TNF-α and p-Tau levels, while enhancing the expression of CD206, IL10 and cognitive functions.
Conclusion: TREM2 played a protective role in IH-induced neuroinflammation and neuronal injury by promoting microglia M2 polarization. IH caused excessive activation of ADAM17 and resulted in augmented degradation of TREM2. Restoring TREM2 expression by inhibiting ADAM17 indicates a potentially promising therapeutic strategy for cognitive impairment in OSA.

Keywords:  ADAM17; TREM2; cognitive impairment; intermittent hypoxia; neuroinflammation; obstructive sleep apnea

DOI:  https://doi.org/10.2147/NSS.S513304
CNS Neurosci Ther. 2025 Sep;31(9): e70595

Electroacupuncture Pretreatment Alleviates Myocardial Ischemia-Reperfusion Injury by Inhibiting Engulfment by Microglia in the Lateral Hypothalamus.

Xiang Zhou, Peiyi Yang, Chaonan Dong, Huimin Chang, Fan Zhang, Qi Shu, Naixuan Wei, Bin Zhang, Yan Wu, Wenjing Shao, Ronglin Cai, Qing Yu.

   AIM: The occurrence of myocardial ischemia-reperfusion injury (MIRI) is accompanied by neuroinflammatory reactions and is closely related to the overactivation of microglia. Currently, effective clinical strategies to prevent MIRI are unclear. This study investigated potential therapeutic targets and the mechanisms of electroacupuncture pretreatment (EA-pre) for MIRI.
METHODS: A MIRI mouse model was established by ligating the left anterior descending branch of the heart for 30 min and reperfusion for 2 h. The mechanisms by which EA-pre alleviates MIRI were investigated through immunofluorescence staining, chemogenetics, and fiber photometry recordings, focusing on the potential involvement of microglia and glutamate (Glu) neurons in the lateral hypothalamic (LH).
RESULTS: EA-pre improves cardiac function in MIRI mice by suppressing microglial activation in the LH. The underlying mechanism likely involves EA-pre inhibition of microglial engulfment of inhibitory synapses around LHGlu neurons. Targeted activation of LHmicroglia reverses EA's inhibitory effect, thereby increasing LHGlu neuronal activity and triggering overactivation of the sympathetic nervous system (SNS), which ultimately exacerbates MIRI.
CONCLUSION: EA-pre inhibits microglial engulfment of inhibitory synapses around LHGlu neurons in MIRI mice, thereby suppressing LHGlu neuronal activity, reducing SNS output, and ultimately exerting cardioprotective effects.

Keywords:  electroacupuncture pretreatment; glutamate neuron; inhibitory synapses; lateral hypothalamus; microglia; myocardial ischemia–reperfusion injury

DOI:  https://doi.org/10.1111/cns.70595
Neuroscience. 2025 Sep 01. pii: S0306-4522(25)00911-X. [Epub ahead of print]585 50-59

TREM2 mediates parkinsonism-like neurodegeneration in carbon disulfide-induced neurotoxicity.

Liu Zhidan, Li Xianjie, Shan Shulin, Jia Qiang, Lou Jianwei, Song Fuyong.

  Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and aggregation of α-Synuclein (α-Syn). While both genetic and environmental factors are implicated in PD pathogenesis, the mechanisms underlying neurodegeneration induced by environmental toxins and associated genetic responses remain largely unknown. Recently, triggering receptor expressed on myeloid cells 2 (TREM2) has been proven to be a critical mediator of toxin-induced motor neuron degeneration. Using GWAS data, this study employed Mendelian randomization analysis and revealed a significant association between elevated serum TREM2 levels and increased risk of secondary PD. Further experiments used 20 male wild-type mice and 20 male TREM2 KO mice exposed to corn oil or carbon disulfide (an environmental toxin associated with PD), respectively, revealed that TREM2 acts as a molecular switch, amplifying environmental neurotoxicity through the excessive activation of microglia. In contrast, Trem2 KO exhibited pronounced neuroprotective effects, including reduced α-Syn aggregation in the substantia nigra, alleviated nigral neuronal structural damage, diminished neuroinflammation, and improved motor coordination in mice. Finally, protein docking and interaction analysis verified that TREM2 recognizes α-Syn and participates in PD-related pathological events, including neuroinflammation and mitochondrial damage. In summary, the present study identifies TREM2 as a pivotal mediator in environmentally induced Parkinsonian syndromes, providing novel insights into the mechanisms underlying neurodegeneration due to environmental toxin exposure and offering potential targets for precise therapeutic interventions.

Keywords:  Environmental neurotoxicity; Microglia activation; Neuroinflammation; Parkinsonism; TREM2

DOI:  https://doi.org/10.1016/j.neuroscience.2025.08.063
Nature. 2025 Sep 03.

PICALM Alzheimer's risk allele causes aberrant lipid droplets in microglia.

Alena Kozlova, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Stanislau Smirnou, Seul Kee Byeon, Christina Thapa, Xiaotong Sun, Kimberley Stephenson, Xiaojie Zhao, Brendan Jamison, Moorthi Ponnusamy, Xin He, Julie A Schneider, Akhilesh Pandey, David A Bennett, Zhiping P Pang, Alan R Sanders, Hugo J Bellen, Gopal Thinakaran, Jubao Duan.

Despite genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) having identified many genetic risk loci1-3, the underlying disease mechanisms remain largely unclear. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Here, using our approach for identifying functional GWAS risk variants showing allele-specific open chromatin, we systematically identified putative causal LOAD-risk variants in human induced pluripotent stem (iPS)-cell-derived neurons, astrocytes and microglia, and linked a PICALM LOAD-risk allele to a microglial-specific role of PICALM in lipid droplet (LD) accumulation. Allele-specific open-chromatin mapping revealed functional risk variants for 26 LOAD-risk loci, mostly specific to microglia. At the microglial-specific PICALM locus, the LOAD-risk allele of the single-nucleotide polymorphism rs10792832 reduced transcription factor (PU.1) binding and PICALM expression, impairing the uptake of amyloid beta (Aβ) and myelin debris. Notably, microglia carrying the PICALM risk allele showed transcriptional enrichment of pathways for cholesterol synthesis and LD formation. Genetic and pharmacological perturbations of microglia further established a causal link between reduced PICALM expression, LD accumulation and phagocytosis deficits. Our work elucidates the selective LOAD vulnerability in microglia at the PICALM locus through detrimental LD accumulation, providing a neurobiological basis that can be exploited for developing clinical interventions.

DOI: https://doi.org/10.1038/s41586-025-09486-x
J Oleo Sci. 2025 ;74(9): 845-857

β-Carotene Suppresses Lipopolysaccharide-induced Nitric Oxide Production in Microglia via Retinoic Acid Receptor-dependent Mechanisms.

Yuki Manabe, Manaka Ueda, Tatsuya Sugawara.

  Carotenoids are one of the common food ingredients with potential anti-inflammatory effects. Screening of carotenoids for their anti-inflammatory effects has predominantly been conducted using macrophages, whereas comparative analyses of their effects on excessive activation of microglia remain limited. This study aimed to evaluate the anti-inflammatory effects of eight different carotenoids in lipopolysaccharide (LPS)-stimulated microglia, focusing on nitric oxide (NO) production suppression and underlying molecular mechanisms. Mouse microglia cell line MG6 was pretreated with carotenoids, followed by stimulation with LPS. Among the tested carotenoids, β-carotene, echinenone, and siphonaxanthin exhibited strong NO-inhibitory effects. Western blot analysis indicated that the effect of siphonaxanthin was mediated by NF-κB inhibition. Lipidomic analysis revealed distinct effects of β-carotene and siphonaxanthin on LPS-stimulated microglia, indicating possible differences in their inhibitory mechanisms. Gene expression analysis showed that β-carotene increased the expression of elongation of very long chain fatty acids (ELOVL) 3, ELOVL4, and fatty acid synthase, while restoring ELOVL6 mRNA expression. These results were consistent with the lipidomic analysis. Pharmacological inhibition studies demonstrated that β-carotene exerted its inhibitory effects via retinoic acid receptor (RAR)-dependent mechanisms, although the involvement of RAR-independent pathways cannot be excluded. Echinenone exhibited RAR-dependent suppression of NO production comparable to that of β-carotene. These findings suggest that carotenoids modulate neuroinflammation through multiple mechanisms, including NF-κB inhibition (e.g. siphonaxanthin), RAR activation (e.g. β-carotene and echinenone), and possibly alternative signaling pathways (e.g. astaxanthin), although the detailed mechanisms remain to be elucidated. Since RAR activation has been shown to improve cognitive function in mouse models of Alzheimer's disease, β-carotene and echinenone may have therapeutic potential in reducing neuroinflammation and preserving cognitive function. Further in vivo studies are necessary to validate these effects.

Keywords:  anti-inflammatory effect; carotenoid; lipidomic analysis; microglia; retinoic acid receptor; β-carotene

DOI:  https://doi.org/10.5650/jos.ess25072
J Ethnopharmacol. 2025 Sep 03. pii: S0378-8741(25)01212-7. [Epub ahead of print] 120520

Buyang Huanwu Decoction Promotes Post-Stroke White Matter Repair via TREM2-Dependent Microglial Phagocytosis and IGF1 Secretion.

Xiaoli Qin, Yunsha Zhang, Jiaxu Liu, Guangxu Xiao, Yuying Guo, Hao Deng, Hongying Hao, Wenzhe Xu, Xueqi Cheng, Linna Zhao, Shixin Xu.

   ETHNOPHARMACOLOGICAL RELEVANCE: White matter injury (WMI) following ischemic stroke represents a critical pathological determinant of persistent neurological impairment, with current therapeutic options remaining limited. Buyang Huanwu Decoction (BYHWD), a time-honored formulation historically deployed in traditional Chinese medicine to address post-stroke sequelae, exhibits documented neuroprotective efficacy; nevertheless, its mechanistic actions governing post-ischemic white matter restoration and remyelination are yet to be fully deciphered.
AIM OF THE STUDY: This study aimed to elucidate whether BYHWD facilitates post-ischemic white matter restoration via TREM2-dependent mechanisms.
MATERIALS AND METHODS: Transient middle cerebral artery occlusion (tMCAO) was induced in mice to model ischemic stroke. Neurological recovery was longitudinally assessed using standardized behavioral tests. Cerebral atrophy and histopathological damage were quantified through hematoxylin-eosin (H&E) and cresyl violet staining. Network pharmacology analysis predicted potential therapeutic targets and pathways, with subsequent validation performed via immunofluorescence techniques. White matter integrity was evaluated by magnetic resonance imaging (MRI) and Luxol fast blue (LFB) myelin staining. Western blotting analyzed striatal TREM2 expression and downstream signaling molecules. Microglial phagocytic activity was determined via immunofluorescence co-localization of myelin basic protein (MBP) with phagocytosis receptors AXL and CD11c. Additional immunofluorescence characterized microglial IGF1 secretion and oligodendrocyte IGF1R expression/proliferation.
RESULTS: BYHWD markedly improved long-term neurological outcomes and mitigated white matter injury in tMCAO mice. Mechanistically, it appeared to enhance TREM2-dependent microglial phagocytosis of myelin debris and to promote microglial IGF1 secretion via activation of the TREM2-ERK1/2 signaling axis, which was associated with increased oligodendrocyte proliferation and remyelination.
CONCLUSION: These findings indicate that BYHWD may facilitate post-stroke white matter repair by modulating TREM2-dependent microglia-oligodendrocyte interactions, supporting its potential as a therapeutic approach for TREM2-associated white matter injury.

Keywords:  Buyang Huanwu Decoction (BYHWD); IGF1; Ischemic stroke; Microglia; TREM2; White matter

DOI:  https://doi.org/10.1016/j.jep.2025.120520
Mol Neurodegener. 2025 Aug 28. 20(1): 94

MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer's disease model.

Hai-Shan Jiao, Yi-Jun Ge, Liang-Yu Huang, Ying Liu, Bang-Sheng Wu, Piao-Piao Lian, Yi-Ning Hao, Shan-Shan Han, Yi-Ting Li, Kai-Min Wu, Chen-Yun Wu, Tian-Lin Cheng, Peng Yuan, Jin-Tai Yu.

   BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia. Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidences indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied.
METHODS: We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis.
RESULTS: We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures.
CONCLUSIONS: Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.

Keywords:  Alzheimer’s disease; MS4A6A; Microglia; Ms4a6d; Neuroinflammation

DOI:  https://doi.org/10.1186/s13024-025-00887-0
Mol Psychiatry. 2025 Sep 02.

Defective Hoxb8 microglia are causative for both chronic anxiety and pathological overgrooming in mice.

Donn A Van Deren, Ben Xu, Naveen Nagarajan, Anne M Boulet, Shuhua Zhang, Mario R Capecchi.

Disruption of the Hoxb8 gene results in chronic anxiety and pathological overgrooming in mice. Using bilateral intracerebral cell transplantation, we demonstrate that mutant Hoxb8 microglia are causative for both behaviors. Mice contain two microglia lineages, Hoxb8 and non-Hoxb8 microglia. We proposed that the two lineages work as a binary system, in opposition to each other with Hoxb8 microglia functioning to reduce anxiety and grooming (function as brakes), whereas non-Hoxb8 microglia increase the levels of both behaviors (function as accelerators). This model makes a strong, unexpected prediction: mice containing only wild-type canonical non-Hoxb8 microglia should exhibit pathological levels of grooming and anxiety. We demonstrate that this is the case, providing strong support for both microglia functioning as a binary system and for the 'Accelerator/Brake' model. Since mice containing only non-Hoxb8 microglia represent mice with a loss of Hoxb8 function due to the absence of Hoxb8 microglia, the more intensive pathology associated with Hoxb8 mutant mice must reflect that mutant mice have both gain and loss of function components. We identify and quantify the relative contribution of each component.

DOI: https://doi.org/10.1038/s41380-025-03190-y
Sci Adv. 2025 Aug 29. 11(35): eadw0128

Cytoskeletal control in adult microglia is essential to restore neurodevelopmental synaptic and cognitive deficits.

Sofie Kessels, Chloë Trippaers, Melanie Mertens, Ibrahim Hamad, Ben Rombaut, Art Janssen, Keerthana Ramanathan, Sam Duwé, Adelaïde M Gharghani, Rune Theuwis, Amber Delbroek, Tim Vangansewinkel, Lisa Berden, Jolien Beeken, Patrick Vandormael, Suresh Poovathingal, Thomas Voets, Markus Kleinewietfeld, Laurent Nguyen, Jack P Antel, Luke M Healy, Sally A Cowley, Koko Ishizuka, Jean-Michel Rigo, Jelle Hendrix, Tim Vanmierlo, Ilse Dewachter, Yeranddy A Alpizar, Akira Sawa, Bert Brône.

Synaptic dysfunction is a hallmark of neurodevelopmental disorders (NDDs), often linked to genes involved in cytoskeletal regulation. While the role of these genes has been extensively studied in neurons, microglial functions such as phagocytosis are also dependent on cytoskeletal dynamics. We demonstrate that disturbance of actin cytoskeletal regulation in microglia, modeled by genetically impairing the scaffold protein Disrupted-in-Schizophrenia 1 (DISC1), which integrates actin-binding proteins, causes a shift in actin regulatory balance favoring filopodial versus lamellipodial actin organization. The resulting microglia-specific dysregulation of actin dynamics leads to excessive uptake of synaptic proteins. Genetically engineered DISC1-deficient mice show diminished hippocampal excitatory transmission and associated spatial memory deficits. Reintroducing wild-type microglia-like cells via bone marrow transplantation in adult DISC1-deficient mice restores the synaptic function of neurons and rescues cognitive performance. These findings reveal a pivotal role for microglial actin cytoskeletal remodeling in preserving synaptic integrity and cognitive health. Targeting microglial cytoskeletal dynamics may effectively address cognitive impairments associated with NDDs, even in adulthood.

DOI: https://doi.org/10.1126/sciadv.adw0128
Brain Behav Immun. 2025 Sep 01. pii: S0889-1591(25)00327-7. [Epub ahead of print] 106092

Microglia-derived exosomes modulate myelin regeneration via activating Nrf2 signaling pathway in oligodendrocyte precursor cells in MS.

Jia-Yi He, Xiao-Yu Ji, Bo Huang, Qing-Qing Sun, Yao Zhang, Rui Gao, Zi-Han Fang, Li-Bin Wang, Yan-Hua Li, Yuan Zhang, Xing Li.

  Demyelination is a prominent feature of multiple sclerosis (MS), where the ability of damaged areas to regenerate myelin is limited. Oligodendrocyte precursor cells (OPCs) accumulate in these areas but struggle to mature into oligodendrocytes (OLGs). Microglia also gather at the lesion site, but their impact on OPCs differentiation is not well understood. Here, we found that miR-155-5p was significantly elevated in the expression profile of exosomes extracted from activated microglia. This miRNA binds to the 3' UTR of the transcription factor Nrf2 in OPCs, inhibiting their differentiation. In a mouse model of demyelination induced by cuprizone, inhibiting miR-155-5p in microglia led to improved motor function recovery, increased the number of mature oligodendrocytes and promoted remyelination. In this study, we highlight a potential new target for treating demyelinating diseases.

Keywords:  Demyelinating disease; Exosomes; Microglia; OPCs; miR-155-5p

DOI:  https://doi.org/10.1016/j.bbi.2025.106092
Cell Rep. 2025 Sep 03. pii: S2211-1247(25)00993-3. [Epub ahead of print]44(9): 116222

Hypoxic stress dysregulates functions of glioma-associated myeloid cells through epigenomic and transcriptional programs.

Monika Dzwigonska, Patrycja Rosa, Szymon Lipiec, Tomasz Obrebski, Gabriela Smyk, Beata Kaza, Salwador Cyranowski, Aleksandra Ellert-Miklaszewska, Agata Kominek, Anna R Malik, Katarzyna Piwocka, Jakub Mieczkowski, Bozena Kaminska, Katarzyna B Leszczynska.

  Hypoxia is a key histopathological feature of glioblastoma, associated with tumor aggressiveness and therapy resistance. Glioma-associated microglia and macrophages (GAMs) are key players in the tumor microenvironment of glioblastoma and acquire immunosuppressive properties during tumor progression. We show that hypoxia alters key GAM identity genes, as it upregulates the expression of monocytic marker lectin galactoside-binding doluble 3 (Lgals3) and downregulates the homeostatic microglial markers purinergic receptor P2Y G-protein coupled 12 (P2ry12) and transmembrane protein 119 (Tmem119) in GAMs co-cultured with glioma cells and in glioblastoma patients' samples. We further identify hypoxia-dependent dysregulation of numerous GAM subtypes and functional markers, which is associated with chromatin accessibility changes, as determined using assay for transposase-accessible chromatin with sequencing (ATAC-seq). Hypoxia upregulates lipid storage-related genes and accumulation of lipid droplets, which can be reversed upon restoration of histone H3 lysine 27 acetylation (H3K27ac) with a histone deacetylase inhibitor. We emphasize the importance of hypoxic stress as a strong intratumoral and epigenomic regulator of myeloid cell functions, which adds a new dimension to the characterization of particular GAM subpopulations.

Keywords:  CP: Cancer; CP: Immunology; chromatin accessibility; epigenomics; glioma; hypoxia; macrophages; microglia; tumor-associated myeloid cells

DOI:  https://doi.org/10.1016/j.celrep.2025.116222
Neuropharmacology. 2025 Aug 29. pii: S0028-3908(25)00370-3. [Epub ahead of print]280 110662

Microglial-derived nitric oxide regulates amygdala synaptic plasticity to drive chronic pain and depression induced by lumbar disc herniation.

Zhenyu Huang, Jiawen Sun, Haokang Li, Zhuang Hu, Haibo Tan, Yuanfei Fu, Linchao Gao, Xin Peng, Hongkan Lou.

  Lumbar disc herniation (LDH) is a major driver of chronic low back pain often accompanied by depression-like behaviors, yet the supraspinal mechanisms that link nociception to affective disturbance remain unclear. Here, we investigated the potential mechanisms by which microglia-derived nitric oxide (NO) modulates synaptic plasticity in the amygdala of a rat model of LDH. Behavioral assessments confirmed the presence of mechanical hyperalgesia and depression-like behaviors in LDH rats. Multi-omics profiling revealed increased L-arginine in CSF and enrichment of cGMP-PKG and glutamatergic, long-term potentiation pathways in the amygdala. Protein-level validation confirmed upregulation of iNOS, NO, cGMP, and PRKG2 in the amygdala. Concurrently, increased levels of IL-1β and TNF-α in both the amygdala and CSF, along with Iba1 and iNOS co-localization in microglia, confirmed a neuroinflammatory microenvironment. Enhanced expression of GRIA1, p-GRIA1, GRIN2B, and p-CaMKII indicated potentiation of excitatory synaptic transmission in the amygdala. In a microglia-neuron co-culture system, conditioned medium from CSF-activated BV2 cells upregulated PRKG2, cGMP, and synaptic plasticity markers in PC12 cells. These effects were abolished by the iNOS inhibitor 1400W and mimicked by the NO donor DETA-NONOate, confirming a mechanistic link between microglial NO and neuronal plasticity. These findings suggested that LDH-induced neuroinflammation activates microglial iNOS in the amygdala, leading to NO elevations that engage the cGMP/PRKG2 pathway and drive pathological excitatory synaptic plasticity. Targeting this neuroimmune pathway may offer novel therapeutic strategies for chronic pain and related depression induced by LDH.

Keywords:  Amygdala; Chronic pain; Depression; Lumbar disc herniation; Microglia; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110662
ACS Nano. 2025 Sep 06.

Nanoparticles Induce Protein Corona Conformational Change to Reshape Intracellular Interactome for Microglial Polarization.

Xin-Yu Xiao, Qian-Wei Luo, Wang-Shu Li, Ze-Kun Chen, Zhuo Yang, Ya-Xuan Zhu, Mu-Rong Lei, Fang-Fang Zhuo, Ming Yu, Tian-Tian Wei, Hong-Wei Jin, Zhong-Yao Li, Zhi-Yuan Lu, Zhu-Qing Zhang, Hua Wang, Yong-Cheng Wang, Qing Xia, Wei Yu, Bo Han, Peng-Fei Tu, Ke-Wu Zeng.

  Nanoparticles bind to proteins in cells selectively and form a protein corona around them. However, the mechanisms of protein conformational changes underlying the interactions between nanoparticles and protein coronas remain poorly understood. In this study, we prepared small molecule self-assembled nanoparticles (Aloin NPs) as a research tool to investigate the allosteric mechanism of protein coronas. Aloin NPs showed a propensity to capture multiple proteins in cells. In particular, Aloin NPs specifically bound to myotrophin (MPTN) as a major protein corona through a multivalent hydrogen bond-mediated nanoprotein interface. Molecular modeling and hydrogen-deuterium exchange mass spectrometry (MS) demonstrated that Aloin NPs promoted a conformational rearrangement of MPTN via a 'finger-unclasping' pattern. We then adapted the APEX2 proximity labeling strategy to investigate the conformation-dependent changes in the MPTN interactome and identified peroxiredoxin 6 (PRDX6) as a key substrate protein of MPTN in microglia. Additionally, we observed that MPTN conformational change-dependent PRDX6 release protected the mitochondrial membrane by reducing reactive oxygen species. Consequently, Aloin NPs effectively inhibited the release of mitochondrial DNA to block the downstream cGAS-STING signaling pathway, thereby reprogramming microglial polarization. In translational medicine, Aloin NPs play a role in protecting neurons from microglia-induced inflammatory injury with no significant adverse effects, ultimately improving Parkinson's disease-associated symptoms. Taken together, our study provides insights into the molecular mechanisms by which nanoparticles regulate the conformational change of protein coronas for human disease therapy.

Keywords:  conformational rearrangement; interactome; microglial polarization; myotrophin; nanoparticles; protein coronas

DOI:  https://doi.org/10.1021/acsnano.5c12630
Commun Biol. 2025 Aug 29. 8(1): 1307

SARS-CoV-2 vaccination during pregnancy enhances offspring hippocampal neurogenesis and working memory via IFN-γ-responsive microglia.

Jiaoling Tang, Fangfang Qi, Juntao Zou, Hao Liu, Zejie Zuo, Lingxiao Wang, Na Wang, Zhihui Li, Ashutosh Kumar, Kaihua Guo, Dandan Hu, Zhibin Yao.

In the face of severe outcomes from COVID-19, vaccines have proven immunogenic and safe and are strongly recommended during pregnancy. This study examines the effects of maternal COVID-19 vaccination on physical development, behavior, and neurogenesis in mouse offspring. After inoculation with inactivated SARS-CoV-2 vaccine (Vero Cell) at gestational day 14.5, antibodies were detected in the serum of dams and pups. At one month of age, offspring of vaccinated dams-but not controls-showed enhanced working memory, increased neural proliferation, neuroblast formation, stem cell activity, and more mature neurons in the dentate gyrus (DG). Luminex assay showed elevated hippocampal IFN-γ and CX3CL1, both linked to neurogenesis and memory. Conditional knockout experiments identified microglial IFNγR1 and CX3CR1 as key mediators of neuronal development through regulating microglial activation and chemotaxis. These findings suggest maternal SARS-CoV-2 vaccination transiently enhances hippocampal neurogenesis and working memory in offspring, without causing neurodevelopmental risk.

DOI: https://doi.org/10.1038/s42003-025-08691-8
Mol Neurodegener. 2025 Aug 29. 20(1): 96

β-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity.

Brandon B Holmes, Thaddeus K Weigel, Jesseca M Chung, Sarah K Kaufman, Brandon I Apresa, James R Byrnes, Kaan S Kumru, Jaime Vaquer-Alicea, Ankit Gupta, Indigo V L Rose, Yun Zhang, Alissa L Nana, Dina Alter, Lea T Grinberg, Salvatore Spina, Kevin K Leung, Bruce L Miller, Carlo Condello, Martin Kampmann, William W Seeley, Jaeda C Coutinho-Budd, James A Wells.



Keywords:   Drosophila model; APOE; Alzheimer’s disease; Amyloid; Astrocytes; GPC4; Heparan sulfate proteoglycans; Microglia; Neuroinflammation; Tau seeding

DOI:  https://doi.org/10.1186/s13024-025-00883-4
Front Genet. 2025 ;16 1593964

A rare intronic c.2654+1G>A mutation in CSF1R-microglial encephalopathy: a case report.

HongYan Wu, JingYu Shi, XiaoShan Wang, Mei Yang, Jing Cai.

   Objective: We report a case of CSF1R-microglial encephalopathy associated with a rare intronic c.2654 + 1G>A mutation, featuring negative diffusion-weighted imaging (DWI) findings and a cerebrospinal fluid (CSF) biomarker profile indicative of Alzheimer's disease-related changes, and we explore the associations between genetic mutations, CSF biomarker alterations, and neuroimaging manifestations.
Methods: This study documents the demographic data, detailed medical history, and clinical manifestations of a patient with CSF1R-microglial encephalopathy. The medical histories of some family members were collected, and the proband underwent whole-exome sequencing (WES) for diagnostic confirmation.
Results: The patient, a 53-year-old woman, presented with early-onset cognitive decline, personality changes, and behavioral abnormalities. Neuropsychological testing revealed severe cognitive impairment, and the CSF biomarker profile suggested Alzheimer's disease-related changes. Cranial MRI showed bilateral, symmetric deep white matter changes, brain atrophy (including corpus callosum thinning), and low signal intensity on DWI. Family history revealed that 3 out of 19 individuals across four generations, including the proband, her aunt, and her sister, developed dementia and progressed to severe cognitive impairment rapidly. WES analysis revealed a heterozygous c.2654 + 1G>A variant in the CSF1R gene (NM_005211.3), confirming a diagnosis of CSF1R-microglial encephalopathy caused by a dominant autosomal mutation in exon 20 of the CSF1R gene.
Conclusion: CSF1R-microglial encephalopathy is a progressive disorder with diverse early clinical presentations, making it prone to misdiagnosis and delayed treatment. This case suggests that, contrary to previous findings, negative DWI results should not exclude CSF1R-microglial encephalopathy. In addition, CSF biomarker profiles in patients with CSF1R-microglial encephalopathy may exhibit Alzheimer's disease-related changes. Early genetic testing is critical, and for genetically linked diseases, testing other family members can help ensure early diagnosis and intervention.

Keywords:  CSF1R (colony stimulating factor 1 receptor); dementia; gene; magnetic resonance imaging; microglia

DOI:  https://doi.org/10.3389/fgene.2025.1593964
Exp Eye Res. 2025 Aug 26. pii: S0014-4835(25)00371-9. [Epub ahead of print]260 110600

Melatonin alleviates retinal damage and visual function impairment by suppressing ROS/TXNIP/NLRP3 signalling and inhibiting microglial activation in rats with optic nerve crush injury.

Chong Liu, Ziqiang Liang, Jiayi Jin, Wanqi Qian, Keli Mao, Yuwei Tang, Yongxin Zheng, Liuxueying Zhong.

  This study aimed to investigate the protective mechanism of melatonin on retinal structure and optic nerve function after optic nerve crush (ONC) in a rat model. SD rats aged 6-8 weeks were used to establish an ONC model. The rats were intraperitoneally administered with melatonin daily after ONC. Loss of retinal ganglion cells (RGCs)/axons was confirmed by haematoxylin & eosin staining, optical coherence tomography, and retina flat mounts. Visual evoked potentials were measured to evaluate optic nerve function. Protein expression was determined by Western blot and immunofluorescence assays, and RT-PCR was performed to assess mRNA transcription. ONC can cause an increase in ROS accumulation in the optic nerve, with elevated expression levels of Iba1, F4/80, thioredoxin-interacting protein (TXNIP), NOD like receptor protein 3 (NLRP3), and cleaved caspase 1, as well as elevated transcription levels of IL-1β/IL-18. ONC can also cause structural damage to the retina, including thinning of the retina, reduction of RGCs and axons, and functional impairment of the optic nerve, including decreased N2‒P2 amplitudes, and prolonged latencies of P2. However, the intraperitoneal injection of melatonin after ONC can reduce the accumulation of ROS in the optic nerve; decrease the expression levels of Iba1, F4/80, TXNIP, NLRP3, and cleaved caspase 1; and also decrease the transcription levels of IL-1β/IL-18. Melatonin treatment also alleviates retinal damage and visual function impairment caused by ONC. These findings suggest that melatonin alleviates retinal damage and visual function impairment after ONC by suppressing the ROS/TXNIP/NLRP3 signalling pathway.

Keywords:  Melatonin; NLRP3 inflammasome; Reactive oxygen species; Thioredoxin-interacting protein; Traumatic optic neuropathy

DOI:  https://doi.org/10.1016/j.exer.2025.110600
J Neuroinflammation. 2025 Aug 28. 22(1): 208

P2X7-CaMKII drives 5-LOX nuclear translocation to impair microglial function after subarachnoid hemorrhage.

Peng-Fei Ding, Jia-Tong Zhang, Xiao-Long Zhu, Yue Cui, Chun-Lei Chen, Xun-Zhi Liu, Jun-Da Shen, Le-Xuan Zou, Yue Lu, Zong Zhuang, Chun-Hua Hang, Wei Li.



Keywords:  5-LOX; Ca2+ ; LTB4/LXA4 ratio; P2X7-CaMKII; Subarachnoid hemorrhage

DOI:  https://doi.org/10.1186/s12974-025-03530-3