bims-microg Biomed News
on Microglia in health and disease
Issue of 2025–08–10
29 papers selected by
Marcus Karlstetter, Universität zu Köln
  1. Microglia-neuron crosstalk via Hex-GM2-MGL2 maintains brain homeostasis.
  2. Microglia regulate GABAergic neurogenesis in prenatal human brain through IGF1.
  3. Therapeutic genetic restoration through allogeneic brain microglia replacement.
  4. Insulin signaling in microglia: A metabolic switch controlling neuroinflammation and amyloid pathology in Alzheimer's disease.
  5. Foam cell-derived exosomes: Messengers between atherosclerosis and microglia.
  6. Alzheimer's disease transcriptional landscape in ex vivo human microglia.
  7. Regulation of Neuroinflammation by Microglial DUBA-IRAK1-IKKβ Signaling Loop.
  8. Engineered peripheral CD4 T cells delivery across the BBB promote intracerebral Treg conversion unleashes microglial phagocytotic activity for Alzheimer's disease treatment.
  9. Mn3O4 nanozyme-based anti-inflammatory therapy modulates microglial phenotype by downregulating TLR4/NOX2 expression and further alleviates Alzheimer's disease pathology.
  10. Harnessing Patient-Derived Antibodies-Induced Microglial Complement 1q Expression: A Novel Therapeutic Approach for Anti-NMDAR Encephalitis.
  11. Spike RBD drives sustained Parkinson's disease progression via microglia-neuron crosstalk-mediated RTP801 upregulation.
  12. Anterior insular cortex regulates depression-like and ASD-like behaviors via the differential contribution of two subsets of microglia.
  13. Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis.
  14. Microglia mediated by LAG3 regulate astrocyte morphogenesis in the brain white matter.
  15. Single-nucleus RNA sequencing reveals the specific molecular signatures of myeloid cells responding to brain injury after microglial replacement.
  16. Microglia exhibit a dynamic response, modulating inducible nitric oxide synthase expression and the production of pro-inflammatory cytokines during experimental cerebral malaria.
  17. Resynchronization of microglial activity in the brain is associated with restoration of motor function in Parkinson's disease.
  18. Modulation of Ryanodine Receptors on Microglial Ramification, Migration, and Phagocytosis in an Alzheimer's Disease Mouse Model.
  19. Reticuline modulates astrocyte and microglial responses to enhance prognosis after traumatic brain injury.
  20. The therapeutic mechanisms of Compound Kushen Injection in relieving cancer-induced bone pain by targeting Nav1.7 and microglial activation.
  21. Analyses of Nogo-Family Genes in Mouse and Human Microglia Omics Datasets Identify LINGO1 as a Candidate Drug Target in Alzheimer's Disease.
  22. Facilitating microglial phagocytosis by which Jiawei Xionggui Decoction alleviates cognitive impairment via TREM2-mediated energy metabolic reprogramming.
  23. Increased spinal adenosine after subacute cervical injury correlates with sustained upregulation of CD39 and CD73 in microglia.
  24. Gamma Oscillation Disruption Induced By Microglial Activation Contributes to Perioperative Neurocognitive Disorders in Aged Mice.
  25. Dysregulated Expression of Inflammasome and Extracellular Matrix Genes in C9orf72-ALS/FTD Microglia.
  26. HDGF derived from Müller cells enhances the activation of microglia in diabetic retinopathy.
  27. HCAR2 Exerts Anti-Depressive Effects on Corticosterone-Induced Depression in Mice by Modulating Microglial Activity.
  28. Swapping microglia to treat ALSP.
  29. Alcohol consumption in P301S mice accelerates gait impairments, modifies aggregation of pathological tau and alters microglia within the hippocampus.
  1. Nature. 2025 Aug 06.
    Microglia-neuron crosstalk via Hex-GM2-MGL2 maintains brain homeostasis.
    Maximilian Frosch, Takashi Shimizu, Emile Wogram, Lukas Amann, Lars Gruber, Ayelén I Groisman, Maximilian Fliegauf, Marius Schwabenland, Chintan Chhatbar, Sabrina Zechel, Hendrik Rosewich, Jutta Gärtner, Francisco J Quintana, Joerg M Buescher, Thomas Blank, Harald Binder, Christine Stadelmann, Johannes J Letzkus, Carsten Hopf, Takahiro Masuda, Klaus-Peter Knobeloch, Marco Prinz.
      As tissue resident macrophages of the central nervous system (CNS) parenchyma, microglia perform diverse essential functions during homeostasis and perturbations1. They primarily interact with neurons via synaptic engulfment and through the rapid elimination of apoptotic cells and nonfunctional synapses2. Here, by combining unbiased lipidomics and high resolution spatial lipid imaging, deep single-cell transcriptome analysis and novel cell type-specific mutants, we identified a previously unknown mode of microglial interaction with neurons. During homeostasis, microglia deliver the lysosomal enzyme β-hexosaminidase (Hex) to neurons for the degradation of the ganglioside GM2 that is integral to maintaining cell membrane organization and function. Absence of Hexb, encoding the β subunit of Hex, in both mice and patients suffering from neurodegenerative Sandhoff disease leads to a massive accumulation of GM2 derivatives in a characteristic spatiotemporal manner3. In mice, neuronal GM2 gangliosides subsequently engage the macrophage galactose-type lectin (MGL)2 receptor on microglia via N-acetylgalactosamine (GalNAc) residues, leading to lethal neurodegeneration. Notably, replacement of microglia with peripherally derived microglia-like cells (MLCs) is able to break this degenerative cycle and fully restore CNS homeostasis. Our results reveal a novel mode of bidirectional microglia-neuron communication centred around GM2 ganglioside turnover, identify a novel microgliopathy and offer novel therapeutic avenues for these maladies.
    DOI:  https://doi.org/10.1038/s41586-025-09477-y
  2. Nature. 2025 Aug 06.
    Microglia regulate GABAergic neurogenesis in prenatal human brain through IGF1.
    Diankun Yu, Samhita Jain, Andi Wangzhou, Beika Zhu, Wenyuan Shao, Elena J Coley-O'Rourke, Stacy De Florencio, JaeYeon Kim, Jennifer Ja-Yoon Choi, Mercedes F Paredes, Tomasz J Nowakowski, Eric J Huang, Xianhua Piao.
      GABAergic neurons are essential cellular components of neural circuits. Their abundance and diversity have increased significantly in the human brain, contributing to the expanded cognitive capacity of humans1. However, the developmental mechanism underlying the extended production of GABAergic neurons in the human brain remains elusive. Here we uncovered the microglial regulation of the sustained proliferation of GABAergic progenitors and neuroblasts in the human medial ganglionic eminence (hMGE). We showed that microglia are preferentially distributed in the proliferating zone and identified insulin-like growth factor 1 (IGF1) and its receptor IGR1R as the predicted top ligand-receptor pair underlying microglia-progenitor communication in the prenatal hMGE. Using our newly developed neuroimmune hMGE organoids, which mimic the hMGE cytoarchitecture and developmental trajectory, we demonstrated that microglia-derived IGF1 promotes progenitor proliferation and production of GABAergic neurons. Conversely, IGF1-neutralizing antibodies and IGF1 knockout human embryonic stem-cell-induced microglia abolish the induced microglia-mediated progenitor proliferation. Together, these findings revealed a previously unappreciated role of microglia-derived IGF1 in promoting the proliferation of neural progenitors and the development of GABAergic neurons in the human brain.
    DOI:  https://doi.org/10.1038/s41586-025-09362-8
  3. Nature. 2025 Aug 06.
    Therapeutic genetic restoration through allogeneic brain microglia replacement.
    Marius Marc-Daniel Mader, Alexa Scavetti, Yongjin Yoo, Aaron Tianyue Chai, Takeshi Uenaka, Marius Wernig.
      Migration of transplanted allogeneic myeloid cells into the brain following systemic hematopoietic stem and progenitor cells transplantation (HCT) holds great promise as a therapeutic modality to correct genetic deficiencies in the brain such as lysosomal storage diseases.1-3 However, the toxic myeloablation required for allogeneic HCT can cause serious, life-threatening side effects limiting its applicability. Moreover, transplanted allogeneic myeloid cells are highly vulnerable to rejection even in an immune-privileged organ like the brain. Here we report a brain-restricted, high-efficiency microglia replacement approach without myeloablative preconditioning. Unlike previous assumptions, we found that hematopoietic stem cells are not required to repopulate the myeloid compartment of the brain environment. In contrast, Sca1- committed progenitor cells were highly efficient to replace microglia following intracerebral injection. This finding enabled the development of brain-restricted preconditioning and avoided long-term peripheral engraftment thus eliminating complications such as graft-vs-host disease. Evaluating its therapeutic potential, we found that our allogeneic microglia replacement method rescues the murine model of Sandhoff disease, a lysosomal storage disease caused by hexosaminidase B deficiency. In support of the translational relevance of this approach, we discovered that human induced pluripotent stem cell-derived myeloid progenitor cells display a similar engraftment potential following brain-restricted conditioning. Our results overcome current limitations of conventional HCT and may pave the way for the development of allogeneic microglial cell therapies for the brain.
    DOI:  https://doi.org/10.1038/s41586-025-09461-6
  4. Cell Metab. 2025 Aug 05. pii: S1550-4131(25)00300-6. [Epub ahead of print]37(8): 1630-1632
    Insulin signaling in microglia: A metabolic switch controlling neuroinflammation and amyloid pathology in Alzheimer's disease.
    Eugenio Barone, D Allan Butterfield.
      Insulin resistance is a risk factor for Alzheimer's disease (AD). Chen et al.1 show that microglial insulin signaling is essential for metabolic homeostasis and immune regulation, while insulin resistance impairs Aβ clearance and promotes neuroinflammation in AD. Their findings reframe AD pathogenesis through a cell-type-specific lens.
    DOI:  https://doi.org/10.1016/j.cmet.2025.06.005
  5. Cell Metab. 2025 Aug 05. pii: S1550-4131(25)00332-8. [Epub ahead of print]37(8): 1626-1628
    Foam cell-derived exosomes: Messengers between atherosclerosis and microglia.
    Yan Yue, Shiping Li, Dezhi Mu.
      Atherosclerosis (AS) is an independent risk factor for vascular cognitive impairment (VCI). Zhang et al.1 revealed that foam cell-derived exosomes transmit redox imbalance and metabolic defects to microglia via the miR-101-3p-Nrf2-Slc2a1 axis, causing microglial dysfunction and exacerbating VCI, uncovering a peripheral-brain link and potential therapeutic targets for AS-induced VCI.
    DOI:  https://doi.org/10.1016/j.cmet.2025.07.005
  6. Nat Neurosci. 2025 Aug 04.
    Alzheimer's disease transcriptional landscape in ex vivo human microglia.
    Roman Kosoy, John F Fullard, Jaroslav Bendl, Steven P Kleopoulos, Zhiping Shao, Stathis Argyriou, Deepika Mathur, Konstantina Psychogyiou, Periklis Malakates, James Vicari, Yixuan Ma, Jack Humphrey, Erica Brophy, Towfique Raj, Pavel Katsel, Georgios Voloudakis, Donghoon Lee, David A Bennett, Vahram Haroutunian, Gabriel E Hoffman, Panos Roussos.
      Microglia are resident immune cells of the brain and are implicated in the etiology of Alzheimer's disease (AD) and other diseases. Yet the cellular and molecular processes regulating their function throughout the course of the disease are poorly understood. Here, we present a transcriptional analysis of primary microglia from 189 human postmortem brains, including 58 healthy aging individuals and 131 with a range of disease phenotypes, such as 63 patients representing the full clinical and pathological spectra of AD. We identified changes associated with multiple AD phenotypes, capturing the severity of dementia and neuropathological lesions. Transcript-level analyses identified additional genes with heterogeneous isoform usage and AD phenotypes. We identified changes in gene-gene coordination in AD, dysregulation of coexpression modules and disease subtypes with distinct gene expression patterns. Taken together, these data further our understanding of the key role that microglia have in AD biology and nominate candidates for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41593-025-02020-2
  7. Adv Sci (Weinh). 2025 Aug 04. e03972
    Regulation of Neuroinflammation by Microglial DUBA-IRAK1-IKKβ Signaling Loop.
    Zhenhu Zhu, Zhongding Li, Kate Lykke Lambertsen, Zijun Cao, Meng Chen, Yanqi Xu, Bettina Hjelm Clausen, Keshuo Jin, Yiting Lu, Fuqi Mei, Xue Du, Kangmin Chen, Huiyuan Bai, Xian Su, Bincheng Zhou, Baohua Liu, Ran Li, Chaoqun Wang, Yuhua Li, Xiang Cai, Dirk Schlüter, Weihong Song, Xu Wang.
      Activation of microglia is closely associated with neuroinflammation. However, the cell-intrinsic molecular mechanisms translating microglia activation into neuroinflammation are only partially understood. Here, it is shown that deubiquitinating enzyme A (DUBA) is upregulated in microglia under neuroinflammatory conditions in both mice and humans. Mechanistically, activation of microglia induces DUBA self-deubiquitination and stabilization, leading to the rapid upregulation of DUBA protein levels. In turn, stabilized DUBA increases proinflammatory gene induction in activated microglia by enhancing the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. Of note, DUBA promotes NF-κB and MAPK activation by stabilizing interleukin-1 receptor activated kinase 1 (IRAK1) through K48 deubiquitination. Importantly, specific ablation of DUBA in microglia mitigates lipopolysaccharide-induced depression-like behavior and ischemic stroke injury in mice by limiting neuroinflammation. Collectively, these findings establish DUBA as a key regulator of microglia in neuroinflammation and uncover novel molecular mechanisms for DUBA in inflammatory signal transduction.
    Keywords:  DUBA; microglia; neuroinflammation; signal transduction; ubiquitination
    DOI:  https://doi.org/10.1002/advs.202503972
  8. Biomaterials. 2025 Jul 28. pii: S0142-9612(25)00493-4. [Epub ahead of print]325 123574
    Engineered peripheral CD4 T cells delivery across the BBB promote intracerebral Treg conversion unleashes microglial phagocytotic activity for Alzheimer's disease treatment.
    Zejie Zuo, Zecong Xiao, Liying Zhang, Shaohui Deng, Xiaofei He, Yating Mu, Pingyi Wang, Yifeng Feng, Zemeng Wang, Shiyin Li, Xiaofeng Yang, Jinghui Xu, Kaihua Guo, Wenhai Guo, Xintao Shuai, Xiquan Hu, Haiqing Zheng.
      Alzheimer's disease (AD) affects thirty million individuals worldwide, but a viable treatment has yet to be identified. During disease progression, peripheral immune cells, including peripheral T cells, infiltrate the brain. Although CD4+ regulatory T cells have been demonstrated to exhibit neuroprotective efficacy in AD, the precise roles of these cells in the brain remain elusive. Here, we report that β-amyloid (Aβ) 1-42 antigen-specific CD4+ T cells spontaneously cross the blood-brain barrier (BBB) into the brain in an APP/PS1 mouse model. To promote parenchymal Treg conversion from infiltrated CD4+ T cells and minimize the perturbations of the brain microenvironment, we engineered an Aβ1-42 antigen-specific CD4+ T cell-based nanodelivery system to release the compound AS2863619, a CDK8/19 inhibitor (eTc-AS), which can bypass the BBB and selectively induce the conversion of CD4+ T cells into Treg cells within the brain region. These cells demonstrated notable pathological amelioration in APP/PS1 mice, in part by interacting with microglia or recruited macrophage via PD-L1/PD-1 signaling. Our study reveals valuable engineered T cell therapies and suggests an immune checkpoint mechanism underlying the neuroprotective function of the Treg-microglia like cell interplay in AD.
    Keywords:  Alzheimer's disease; Blood-brain barrier; Engineered T cells; Microglia; Phagocytosis; T regulatory cells; β-amyloid
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123574
  9. Theranostics. 2025 ;15(15): 7467-7488
    Mn3O4 nanozyme-based anti-inflammatory therapy modulates microglial phenotype by downregulating TLR4/NOX2 expression and further alleviates Alzheimer's disease pathology.
    Jun Xie, Kai Cao, Luman Liu, Liding Zhang, Ying Yang, Hui Gong, Haiming Luo.
      Rationale: Evidence shows that neuroinflammation mediated by microglial activation plays an important role in Alzheimer's disease (AD) pathogenesis. However, the relationship between microglial phenotype and fibrillar β-amyloid (fAβ) pathology in anti-inflammatory treatment of AD remains unclear. Methods: We designed a water-soluble Mn3O4 nanozymes and demonstrated its ability to reverse lipopolysaccharide (LPS)-induced microglial transition from M1 to M2 phenotype by clearing reactive oxygen species (ROS). Results: In 5×FAD transgenic mice, intranasal (IN) instillation of Mn3O4 nanozymes initially promoted M2 microglial polarization and significantly reduced neuroinflammation after 4 weeks of treatment. After 8 weeks of continuous treatment, they further alleviate fAβ pathology and improved learning and memory deficits in 5×FAD mice. The excellent anti-inflammatory effect of Mn3O4 nanozymes is achieved by inhibiting the Toll-like receptor 4 (TLR4)/nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase isoform 2 (NOX2) pathway to clear ROS. Conclusions: This study reveals the molecular mechanism of Mn3O4 nanozymes modulating microglia phenotype to attenuate neuroinflammation primarily through inhibition of the TLR4/NOX2 pathway and highlights the temporal sequence of anti-inflammatory treatment in regulating microglial phenotype and improving fAβ pathology, providing new insights for the anti-inflammatory treatment of AD and other neurological diseases.
    Keywords:  Alzheimer's disease; anti-inflammatory treatment; microglial phenotype; nanozymes; reactive oxygen species
    DOI:  https://doi.org/10.7150/thno.112213
  10. Mol Ther. 2025 Aug 06. pii: S1525-0016(25)00631-8. [Epub ahead of print]
    Harnessing Patient-Derived Antibodies-Induced Microglial Complement 1q Expression: A Novel Therapeutic Approach for Anti-NMDAR Encephalitis.
    Bingtian Xu, Yunmeng Bai, Zhuhe Liu, Jiahui Li, Kechun Chen, Yinyu Zi, Yuanyuan Wang, Jiangping Xu, Haitao Wang, Fu-Dong Shi, Jigang Wang, Honghao Wang.
      Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is the most prevalent autoimmune encephalitis caused by antibodies against the NMDAR subunit GluN1. Clinical evidence suggests that NMDARE is characterized by microglial activation, but the role of this activation remains unclear. In this study, single-nucleus RNA sequencing of the hippocampus from NMDARE mice revealed an upregulation of microglial Complement 1q (C1q) levels. Clinically, we observed elevated C1q in the cerebrospinal fluid of NMDARE patients. Our studies showed that microglial cells express NMDAR, and antibodies from NMDARE patients act on microglia, inducing NMDAR internalization at the microglial membrane and triggering microglial C1q expression. Notably, silencing C1q attenuated the microglial activation induced by NMDAR antibodies, whereas C1q overexpression exacerbated this process. In vivo, C1q microglial knockout and knockdown in mice both showed reduced damage following NMDARE, while C1q overexpression in the hippocampus intensified pathological effects. Most promisingly, neutralizing antibodies against C1q significantly mitigated injury in NMDARE mice. In summary, our findings highlight the therapeutic potential of inhibiting C1q to counteract NMDARE-induced injury.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.08.001
  11. J Adv Res. 2025 Aug 07. pii: S2090-1232(25)00589-2. [Epub ahead of print]
    Spike RBD drives sustained Parkinson's disease progression via microglia-neuron crosstalk-mediated RTP801 upregulation.
    Sha-Sha Wang, Ruo-Lan Yuan, Wen-Fei Wang, Ye Peng, Kai-Chao Hu, Wen-Bin He, Ya-Xian Zhao, Xu Yan, Zhao Zhang, Shi-Feng Chu, Nai-Hong Chen.
       INTRODUCTION: Emerging evidence highlights the exacerbation and sustained Parkinson's disease (PD) progression following COVID-19. The SARS-CoV-2 spike receptor-binding domain (RBD), which can persist in the brain post-infection, is a likely contributor, but how it drives this neuropathology is unclear.
    OBJECTIVES: To elucidate the underlying mechanisms of long COVID's impact on PD and identify mechanism that contribute to the continuous progression of PD.
    METHODS: The SARS-CoV-2 spike RBD was stereotactically injected into the substantia nigra pars compacta of α-synuclein (αSyn) A53T mice within a chronic stress-genetic susceptibility model. We characterized the pathological impact of RBD using motor and non-motor behavioral tests, fMRI-based functional connectivity, in vivo electrophysiology, immunofluorescence, and αSyn aggregate analysis. To elucidate the underlying mechanisms, we then employed RNA-sequencing, transmission electron microscopy, microglial depletion, and comparative studies in αSyn A53T mice lacking RTP801 (αSyn A53T+; RTP801-/-).
    RESULTS: RBD accelerated PD-related motor and non-motor symptom deterioration, impaired brain functional connectivity, and reduced neuronal excitability. It exacerbated dopaminergic neuron degeneration and αSyn aggregation. RTP801 was identified as a critical mediator of RBD-induced PD progression, with its sustained upregulation in dopaminergic neurons dependent on microglial activation. Mechanistically, initially activates microglia induced an increase in neuronal RTP801 via IL-6 and IL-8. RBD leaded to mitochondrial dysfunction, mtDNA release, and activation of the cGAS-STING pathway between neurons and microglia, triggering a mtDNA-cGAS-STING-IFNβ/RTP801 feedback loop, driving neurodegeneration.
    CONCLUSIONS: Our findings demonstrate that SARS-CoV-2 RBD exacerbates PD progression through a pathogenic crosstalk between microglia and neurons. This neurotoxic signaling is mediated by a mitochondrial mtDNA-cGAS-STING-IFNβ/RTP801 axis. Targeting RTP801 or the STING pathway may therefore represent a promising therapeutic strategy to mitigate long COVID-associated progression of PD.
    Keywords:  Long COVID; Parkinson’s disease; Psychological stress; RBD; RTP801; cGAS-STING
    DOI:  https://doi.org/10.1016/j.jare.2025.07.060
  12. Mol Psychiatry. 2025 Aug 06.
    Anterior insular cortex regulates depression-like and ASD-like behaviors via the differential contribution of two subsets of microglia.
    Qiao-Ming Zhang, Yan-Fen Chen, Yun-Yun Xing, Mengliu Yang, Na Li, Xi Jiang, Hongyan Gao, Si-Yao Lu, Jun Yao.
      The anterior insular cortex (aIC) is involved in multiple neuropsychiatric disorders. Here, using the Cntnap2-deficient autism spectrum disorder (ASD) mouse model and the chronic social defect stress (CSDS)-induced depression mouse model, we show that two subpopulations of microglia in the mouse aIC played differential roles in ASD-like and depression-like behavioral phenotypes differentially. The Cx3cr1+ microglia had morphological deficits in the Cntnap2-deficient mice and were involved in social deficits and restricted repetitive behaviors, while the Tmem119+ microglia had morphological deficits in the CSDS-induced mice and contributed to impairments in sucrose preference and forced swim performance. Further, we showed that the two subsets of microglia had differential features in morphology, transcriptional profiles, electrophysiological properties, and impacts on synaptic functions. Using proteomic and metabonomic analyses, we identified two secretory factors, Fbl and Hp1bp3, that were crucial for the dysfunctions of the Cx3cr1+ and Tmem119+ microglia, respectively. Finally, we verified that Fbl and Hp1bp3 played essential roles in the behavioral deficits of the Cntnap2-deficient and the CSDS-induced mice, respectively. Our study can help understand the contribution of microglia and the aIC to neuropsychiatric-like behaviors.
    DOI:  https://doi.org/10.1038/s41380-025-03139-1
  13. Mil Med Res. 2025 Aug 05. 12(1): 46
    Decreased IL-33 in the brain following repetitive mild traumatic brain injury contributes to cognitive impairment by inhibiting microglial phagocytosis.
    Ze-Xi Jia, Meng-Tian Guo, Mei-Mei Li, Pan Liao, Bo Yan, Wei Zhang, Fang-Yuan Cheng, Ya-Ru Liu, Zi-Han Zhang, Cheng Wei, Jie Zhou, Fang-Lian Chen, Ping Lei, Xin-Tong Ge.
       BACKGROUND: Repetitive mild traumatic brain injury (rmTBI) is a significant risk factor for neurodegeneration, characterized by pathological protein deposition and persistent neuroinflammation. Research has observed increased interleukin-33 (IL-33) levels in the peripheral blood of patients with rmTBI, suggesting IL-33 may participate in regulating the pathological development of rmTBI. The study aims to elucidate the impact and mechanism of IL-33 in the progression of neuropathology following rmTBI, and to explore its potential as a therapeutic target to improve the neurological outcome.
    METHODS: The study employed an rmTBI mouse model using the wild-type (WT) and IL-33 knockout mice. Cognitive function was assessed via the Y-maze and Barnes tests. The main cell type expressing IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), was then investigated in the mouse brain through immunofluorescence colocalization. As the primary neural cell responsible for ST2 expression, microglia were studied in vitro using the BV2 cell line. The effects of lipid droplets (LDs) accumulation and amyloid-beta (Aβ) phagocytosis were measured to elucidate the impact of IL-33 on BV2 cells' phagocytosis. Additionally, HT22 neuronal apoptosis was assessed by flow cytometry. Finally, the cognitive effects of intranasal administration of IL-33 were evaluated in mice.
    RESULTS: IL-33KO mice exhibited pronounced cognitive impairment after rmTBI. In the mouse brain, astrocytes were identified as the primary source of IL-33 secretion, while microglia predominantly expressed ST2. Transcriptome sequencing revealed that IL-33 significantly influenced phagocytosis function. IL-33 mitigated LDs accumulation in BV2 cells and enhanced Aβ phagocytosis in vitro. In addition, the culture medium of BV2 cells with activated IL-33/ST2 signaling reduced HT22 neuronal apoptosis and axonal damage. Furthermore, intranasal administration of IL-33 was observed to be effective in alleviating neurodegeneration and cognitive outcome of rmTBI mice.
    CONCLUSIONS: Dysfunction of the IL-33/ST2 axis following rmTBI leads to cognitive dysfunction via impairing microglial phagocytosis capacity and promoting neuronal damage. IL-33 would be a promising therapeutic target for alleviating neurodegeneration following rmTBI.
    Keywords:  Cognition; Interleukin-33 (IL-33); Microglia; Repetitive mild traumatic brain injury (rmTBI)
    DOI:  https://doi.org/10.1186/s40779-025-00631-1
  14. Cell Rep. 2025 Aug 05. pii: S2211-1247(25)00883-6. [Epub ahead of print]44(8): 116112
    Microglia mediated by LAG3 regulate astrocyte morphogenesis in the brain white matter.
    Sihan Li, Mengtian Zhang, Jie Qin, Yanyan Wang, Runhua Yang, Fen Ji, Jianwei Jiao.
      Microglia display dynamic morphological and functional heterogeneity during brain development, yet the molecular mechanisms governing their regional specialization remain unclear. We report that lymphocyte-activation gene 3 (Lag3) is highly expressed in white matter amoeboid microglia at postnatal day 7. Conditional deletion of Lag3 in microglia (Lag3cKO-Cx3) specifically reduces microglial density and activation in the white matter, without affecting gray matter microglia. This microglial alteration further reduces the morphological complexity of the surrounding astrocytes in Lag3cKO-Cx3 mice but has no significant effects on oligodendrocytes or neuronal axons. Behavioral tests show no deficits despite these glial abnormalities. Mechanistically, reduced p38MAPK phosphorylation in the white matter microglia of Lag3cKO-Cx3 mice decreases the expression of GITRL, a downstream ligand interacting with astrocytes, leading to dysregulation of mTOR signaling in astrocytes. Thus, Lag3-mediated regulation of postnatal white matter amoeboid microglial abundance and activation influences astrocyte morphology while revealing microglial heterogeneity and microglia-astrocyte communication.
    Keywords:  CP: Neuroscience; GITRL; Lag3; astrocyte morphogenesis; microglia heterogeneity; white matter
    DOI:  https://doi.org/10.1016/j.celrep.2025.116112
  15. Front Immunol. 2025 ;16 1625673
    Single-nucleus RNA sequencing reveals the specific molecular signatures of myeloid cells responding to brain injury after microglial replacement.
    Xiao-Yi Xiong, Haicheng Yuan, Ying Mu, Yi He, Fang Xie, Xiao-Shuang Feng, Jia-Xin Xie, Xin-Ru Pan, Yu-Fei Wang, Jian Gong, Xiaoming Zheng, Peng-Fei Wang.
       Background: Myeloid cells, such as resident microglia (MG), infiltrating monocytes (Mo), macrophages (MΦ), and CNS border-associated macrophages (BAM) in the brain, participate in aged brain injury. Aged microglial replacement is protective against brain injury in aged mice; however, whether/how the molecular changes in myeloid cells are affected by this replacement in injured brains remains unclear.
    Methods: Aged microglia in mice were eliminated by PLX3397 for 21 consecutive days and repopulated following withdrawal for 21 days; then, intracerebral hemorrhage (ICH) models were constructed. Then, a single-nucleus transcriptomic analysis of acutely injured brains in aged mice with microglial replacement was performed.
    Results: We observed similarities but strong divergence in the composition and molecular change features of myeloid cells between the replacement (Rep) and control (Con) groups, indicating retention of the core transcriptome and development of differential genes in myeloid cells after microglial replacement in response to brain injury. Both MG and Mo/MΦ experience modification of immune responses after microglial repopulation, with more prominent changes in MG. Gene Ontology (GO) analysis showed that one term directly related to the "immune response" was shared between upregulated genes in Rep-MG and Rep-Mo/MΦ, while the other terms related to immune functions and other biofunctions were different between Rep-MG and Rep-Mo/MΦ, indicative of significantly different immune responses to brain injury between MG and MΦ. Furthermore, the trajectory analysis showed a significant transition from aged to young state in Rep-MG compared to only a modest youthful shift in Rep-Mo/MΦ, suggesting a rejuvenation process of aged microglia and macrophages toward young ones in response to brain injury after the treatment of microglial replacement.
    Conclusion: Our data indicate that microglial replacement-induced changes in the molecular heterogeneity and state transition of myeloid cells may be neuroprotective against acute brain injury.
    Keywords:  brain injury; intracerebral hemorrhage; microglial replacement; myeloid cells; snRNA-seq
    DOI:  https://doi.org/10.3389/fimmu.2025.1625673
  16. Front Immunol. 2025 ;16 1494418
    Microglia exhibit a dynamic response, modulating inducible nitric oxide synthase expression and the production of pro-inflammatory cytokines during experimental cerebral malaria.
    Lucas Freire-Antunes, Uyla Ornellas-Garcia, Marcos Rangel-Ferreira, Mônica Lucas Ribeiro-Almeida, Leonardo José Moura Carvalho, Cláudio Tadeu Daniel-Ribeiro, Flávia Lima Ribeiro-Gomes.
      Microglia play a fundamental role in maintaining central nervous system homeostasis by monitoring brain tissue for physical, structural, and biochemical alterations. Its involvement in the pathogenesis of various neurological disorders is well documented. However, the role of microglia in cerebral malaria, a disease associated with high mortality and long-term neurological sequelae, remains poorly understood. In this study, we utilized the classical model of experimental cerebral malaria (Plasmodium berghei ANKA-infected C57BL/6 mice) to investigate the dynamics and response of resident brain cell populations, particularly microglia, and the influx of other leukocytes during the development of experimental cerebral malaria. By employing flow cytometry and established markers for different leukocyte populations, we were able to discern and document an increase in the number of Ly6C+ T cells (CD45hiCD11b-CD3+ cells), inflammatory monocytes (CD45hiCD11b+TMEM119-CD206- cells), resident macrophages (CD45hiCD11b+TMEM119-CD206+ cells), and microglia (CD45lowCD11b+ TMEM119+CD206- cells) following infection. Moreover, our ex vivo analysis demonstrated an increment in the overall number of inflammatory monocytes, resident macrophages and microglia expressing inducible nitric oxide synthase (iNOS), in addition to those producing interleukin-1β or TNF. These findings highlight the pronounced reactivity of microglia in experimental cerebral malaria and provide valuable information on cell dynamics and immune responses in the brain.
    Keywords:  IL-1β; TNF; experimental cerebral malaria; iNOS; macrophages; malaria; microglia; nitric oxide
    DOI:  https://doi.org/10.3389/fimmu.2025.1494418
  17. Commun Biol. 2025 Aug 09. 8(1): 1188
    Resynchronization of microglial activity in the brain is associated with restoration of motor function in Parkinson's disease.
    Peizhen Ye, Lei Bi, Yifan Qiu, Min Yang, Yongshan Liu, Yuyi Hou, Pengcheng Zheng, Xiaojuan Cao, Jing Su, Hongjun Jin.
      Neuroinflammation is a key factor in Parkinson's disease (PD) pathogenesis. However, the regional heterogeneity of biomarkers related to inflammation in PD is less well defined. We developed [18F]GSK PET imaging to quantify neuroinflammation via the P2X7 receptor (P2X7R) in A53T PD male mice and wild-type (WT) male mice. Montelukast (MK) was administered to mice, and weekly behavior tests confirmed MK's efficacy. [18F]L-DOPA/[18F]GSK PET, motor testing, autoradiography, and immunofluorescence were performed after MK treatments. MK improved motor function and reduced the brain uptake of [18F]GSK, indicating resynchronization of regional microglial activity. The whole brain uptake of [18F]GSK was correlated with motor functional restoration, while [18F]L-DOPA PET was not. Overall, our study indicated that brain mapping of [18F]GSK PET is beneficial for exploring P2X7R-related neuroinflammation, which is correspondent to motor function in PD.
    DOI:  https://doi.org/10.1038/s42003-025-08602-x
  18. Neurosci Bull. 2025 Aug 06.
    Modulation of Ryanodine Receptors on Microglial Ramification, Migration, and Phagocytosis in an Alzheimer's Disease Mouse Model.
    Yulin Ouyang, Zihao Chen, Qiang Huang, Hai Zhang, Haolin Song, Xinnian Wang, Wenxiu Dong, Yong Tang, Najeebullah Shah, Shimin Shuai, Yang Zhan.
      Microglial functions are linked to Ca2+ signaling, with endoplasmic reticulum (ER) calcium stores playing a crucial role. Microglial abnormality is a hallmark of Alzheimer's disease (AD), but how ER Ca2+ receptors regulate microglial functions under physiological and AD conditions remains unclear. We found reduced ryanodine receptor 2 (Ryr2) expression in microglia from an AD mouse model. Modulation of RyR2 using S107, a RyR-Calstabin stabilizer, blunted spontaneous Ca2+ transients in controls and normalized Ca2+ transients in AD mice. S107 enhanced ATP-induced migration and phagocytosis while reducing ramification in control microglia; however, these effects were absent in AD microglia. Our findings indicate that RyR2 stabilization promotes an activation state shift in control microglia, a mechanism impaired in AD. These results highlight the role of ER Ca2+ receptors in both homeostatic and AD microglia, providing insights into microglial Ca2+ malfunctions in AD.
    Keywords:  Alzheimer’s disease; ER calcium signaling; Microglia; ORAI; Ryanodine receptor
    DOI:  https://doi.org/10.1007/s12264-025-01469-2
  19. Neurotherapeutics. 2025 Aug 05. pii: S1878-7479(25)00187-4. [Epub ahead of print] e00709
    Reticuline modulates astrocyte and microglial responses to enhance prognosis after traumatic brain injury.
    Shuhui Xu, Jue Zhu, Jiajia Wen, Chenxing Wang, Xuanfeng Chen, Weiquan Liao, Zhichao Lu, Ziheng Wang, Peipei Gong.
      Traumatic brain injury (TBI) poses a serious threat to public health due to its high disability and mortality rates. Therefore, it is crucial to explore effective therapeutic strategies. Studies have shown that reticuline may exert a cardioprotective effect by blocking the JAK-STAT signaling pathway, but its effect in TBI has not been explored. Therefore, this study aimed to evaluate the potential clinical value of reticuline after TBI and its impact on the inflammatory quiescent state. This study assessed the therapeutic effect of reticuline administered intraperitoneally using the controlled cortical impact (CCI) model in adult rats. In addition, to clarify the mechanism of action of reticuline, we used Colivelin, a STAT3 agonist, to restore the function of related signal pathways and explore its intervention effect. The study showed that reticuline inhibited neuroinflammation and promoted neurological function recovery after TBI by regulating the JAK-STAT signaling pathway, reducing the toxic response of astrocytes and microglia while retaining its neuroprotective effect. In summary, this study reveals that reticuline may promote neural repair after TBI through a JAK-STAT-dependent anti-inflammatory effect. Our findings further expand its potential application value in brain injury treatment and provide new ideas for intervention strategies for TBI.
    Keywords:  Astrocyte; Microglia; Neuroinflammation; Neurological function; Reticuline; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.neurot.2025.e00709
  20. J Ethnopharmacol. 2025 Aug 04. pii: S0378-8741(25)01059-1. [Epub ahead of print] 120367
    The therapeutic mechanisms of Compound Kushen Injection in relieving cancer-induced bone pain by targeting Nav1.7 and microglial activation.
    Li Gao, Qian-Wen Li, Xin-Yue Zhang, Rong-Li You, Xue-Mei Qin, Wen-Jie Qin.
       ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM) theory, Compound Kushen Injection (CKI) possesses multiple therapeutic effects, including heat-clearing, detoxification, blood-cooling, dampness-resolving, and pain relief. CKI has been used clinically for 30 years as an adjunctive drug alongside chemotherapy and radiotherapy agents for cancer treatment. However, the effects of CKI on cancer-induced bone pain (CIBP) and potential mechanisms remain poorly understood.
    AIM OF THE STUDY: To investigate the therapeutic effects of CKI on CIBP and elucidate its mechanisms based on Nav1.7 and microglial activation.
    METHODS: The therapeutic effect of CKI in CIBP was systematically evaluated using behavioral tests, X-ray, HE staining, Micro-CT and TRAP staining. The mechanisms of CKI were explored by examining Nav1.7 expression and microglial activation both in vivo and in vitro. We further examined the effects of CKI on the blood-spinal cord barrier (BSCB) damage in CIBP rats. Inspired by the mechanisms of CKI, we further investigated whether inhibition of Nav1.7 could inhibit microglial activation and attenuates BSCB damage, thereby alleviating CIBP.
    RESULTS: In CIBP rats, CKI significantly alleviated pain hypersensitivity. Furthermore, CKI enhanced trabecular bone quantity and continuity, reduced trabecular separation, and decreased the number of TRAP-positive cells, thereby preserving tibial structural integrity. Notably, CKI significantly reduced Nav1.7 expression in the spinal cord and DRG. Meanwhile, CKI and its primary active ingredients, matrine and oxymatrine, dose-dependently suppressed Nav1.7 expression in vitro. Additionally, CKI attenuated microglial hyperactivation, restored the expression of spinal barrier proteins (Claudin1 and Occludin) in the spinal cord, and disrupted the vicious cycle between microglial activation and BSCB damage. In LPS-activated BV-2 microglial cells, CKI, matrine and oxymatrine inhibited the release of NO, and restored the balance of anti-inflammatory and pro-inflammatory (IL-4/TNF-α), thereby inhibiting BV-2 cell activation. Moreover, PF05089771 relieved CIBP by significantly decreasing osteoclasts number, suppressing microglial activation in the spinal cord, and attenuating BSCB damage.
    CONCLUSION: CKI significantly alleviated CIBP likely through downregulating Nav1.7, thereby suppressing microglial activation and attenuating BSCB damage. Overall, this study not only uncovered the novel mechanisms of CKI in combating CIBP, but also unveiled Nav1.7 as a promising pharmacological target for CIBP therapy.
    Keywords:  Compound Kushen Injection; Nav1.7; blood-spinal cord barrier; cancer-induced bone pain; microglia
    DOI:  https://doi.org/10.1016/j.jep.2025.120367
  21. Curr Neuropharmacol. 2025 Jul 30.
    Analyses of Nogo-Family Genes in Mouse and Human Microglia Omics Datasets Identify LINGO1 as a Candidate Drug Target in Alzheimer's Disease.
    Glotfelty Elliot J, Tobias E Karlsson, Lars Olson, Brandon K Harvey, Nigel H Greig, Luis B Tovar-Y-Romo.
      Microglia are the innate immune cells of the brain. Recent single-cell and nucleus sequencing, along with other omics technologies, are leading the way for discoveries related to microglial function and diversity. The Nogo-signaling system is a prime target for investigation with these tools as it has previously been neglected in microglia. The Nogo-signaling system comprises approximately 20 proteins, including ligands, receptors, co-receptors, and endogenous inhibitors, which are known for their neuronal plasticity-restricting properties via RhoA and ROCK1/ROCK2 activation. It has recently been implicated in microglial function. In this study, expression patterns of Nogofamily genes in the mouse and human brain are explored. In mice, the focus is on brain cell type enrichment, patterns of expression in microglia from embryonic stages to adulthood, sex differences, and changes in expression in both acute and chronic inflammatory contexts, using publicly available RNA-seq and RiboTag translational profiling datasets. The differential expression of Nogo-family genes across age, sex, and disease/injury in mice has been identified. To analyze human microglia, a new tool, the CZ CellxGene Discover, was utilized to aggregate 21 single-cell sequencing datasets of human brain cells from Alzheimer's disease (AD) and control patients. In humans, Lingo1 is highly enriched in human AD microglia, a previously undescribed finding. The Alzheimer's Cell Atlas (TACA) was used to further verify whether this enrichment correlates with disease state, severity of human AD diagnosis, or sex of patients. The current work provides a comprehensive analysis of Nogo-family genes in microglia and identifies Lingo1 as a potential therapeutic target for AD.
    Keywords:  Alzheimer’s disease.; CZ cellxgene discover; Lingo1; TACA; inflammation; microglia; nogo; ribotag; transcriptomics
    DOI:  https://doi.org/10.2174/011570159X359944250722061312
  22. Chin J Nat Med. 2025 Aug;pii: S1875-5364(25)60927-7. [Epub ahead of print]23(8): 909-919
    Facilitating microglial phagocytosis by which Jiawei Xionggui Decoction alleviates cognitive impairment via TREM2-mediated energy metabolic reprogramming.
    Wen Wen, Jie Chen, Junbao Xiang, Shiqi Zhang, Jingru Liu, Jie Wang, Ping Wang, Shijun Xu.
      Triggering receptor expressed on myeloid cells 2 (TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta (Aβ) clearance in Alzheimer's disease (AD). Energy metabolic reprogramming (EMR) in microglia induced by TREM2 presents therapeutic targets for cognitive impairment in AD. Jiawei Xionggui Decoction (JWXG) has demonstrated effectiveness in enhancing energy supply, protecting microglia, and mitigating cognitive impairment in APP/PS1 mice. However, the mechanism by which JWXG enhances Aβ phagocytosis through TREM2-mediated EMR in microglia remains unclear. This study investigates how JWXG facilitates microglial phagocytosis and alleviates cognitive deficits in AD through TREM2-mediated EMR. Microglial phagocytosis was evaluated through immunofluorescence staining in vitro and in vivo. The EMR level of microglia was assessed using high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA) kits. The TREM2/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway was analyzed using Western blotting in BV2 cells. TREM2-/- BV2 cells were utilized for reverse validation experiments. The Aβ burden, neuropathological features, and cognitive ability in APP/PS1 mice were evaluated using ELISA kits, immunohistochemistry (IHC), and the Morris water maze (MWM) test. JWXG enhanced both the phagocytosis of EMR disorder-BV2 cells (EMRD-BV2) and increased EMR levels. Notably, these effects were significantly reversed in TREM2-/- BV2 cells. JWXG elevated TREM2 expression, adenosine triphosphate (ATP) levels, and microglial phagocytosis in APP/PS1 mice. Additionally, JWXG reduced Aβ-burden, neuropathological lesions, and cognitive deficits in APP/PS1 mice. In conclusion, JWXG promoted TREM2-induced EMR and enhanced microglial phagocytosis, thereby reducing Aβ deposition, improving neuropathological lesions, and alleviating cognitive deficits.
    Keywords:  Akt/mTOR/HIF-1α; Energy metabolic reprogramming; Jiawei Xionggui Decoction; Microglial phagocytosis; Triggering receptor expressed on myeloid cells 2 (TREM2)
    DOI:  https://doi.org/10.1016/S1875-5364(25)60927-7
  23. Neurochem Int. 2025 Aug 05. pii: S0197-0186(25)00103-2. [Epub ahead of print]189 106030
    Increased spinal adenosine after subacute cervical injury correlates with sustained upregulation of CD39 and CD73 in microglia.
    Mackenzie R Berschel, Maria Nikodemova, Jose R Oberto, Alexandria B Marciante, Alysha Michaelson, Gordon S Mitchell.
      Cervical spinal cord injuries (cSCI) are associated with decreased breathing ability. Although no treatment options are currently available, moderate acute intermittent hypoxia (mAIH) is a promising therapeutic modality to improve breathing function after cSCI. Moderate AIH elicits phrenic motor plasticity via distinct, competing serotonin- or adenosine-driven mechanisms that interact via powerful crosstalk inhibition that constrains or even abolishes plasticity. The dominant mechanism driving plasticity depends on the spinal serotonin/adenosine balance. Shortly after cSCI, repeated AIH exposure elicits plasticity via an adenosine-dependent mechanism but reverts to serotonin-dominance with chronic cSCI. In healthy CNS, microglia regulate AIH-induced phrenic motor plasticity via enzymatic activities of ectonucleotidases (CD39, CD73) by converting extracellular ATP to adenosine. We hypothesized that cSCI increases microglial ectonucleotidase expression, elevating adenosine levels that may alter therapeutic responses to mAIH post-cSCI. We assessed microglial CD39 and CD73 expression at the subacute (1 & 2 weeks) and chronic (8 weeks) stages post C2-hemisection, both at the injury site (C1-C3) and in spinal segments containing phrenic motor neurons below the injury (C3-C6). Both enzymes were upregulated (mRNA & protein) 1- and 2-weeks post injury but returned to baseline by 8 weeks. In association, spinal adenosine increased significantly at 2, but not 8 weeks post-injury. Further, microglial CD39 and CD73 expression strongly correlate with P2Y12 receptor expression. Thus, shifting adenosine levels between subacute and early chronic cSCI may impact mechanism regulating mAIH-induced respiratory motor plasticity and breathing recovery at different times post-cSCI.
    Keywords:  Adenosine; CD39; CD73; Ectonucleotidases; Microglia; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.neuint.2025.106030
  24. J Mol Neurosci. 2025 Aug 02. 75(3): 97
    Gamma Oscillation Disruption Induced By Microglial Activation Contributes to Perioperative Neurocognitive Disorders in Aged Mice.
    Shiyu Hao, Qidi Zhang, Xianzheng Zhang, Zunsai Feng, Jiangnan Wu, Ziqing Xu, Jingjing Li, Gongming Wang.
      Perioperative neurocognitive disorder (PND) is a prevalent postoperative complication of the central nervous system (CNS) in elderly patients. Advanced age is an independent risk factor for developing PND. Microglia are essential immune cells in the CNS and play a critical role in neuroinflammation. The activation of microglia is closely linked to PND, although the precise mechanism remains unclear. Gamma oscillations (30-100 Hz) are associated with higher cognitive functions, including attention. The aim of this study was to investigate the mechanism by which microglial activation in PND disrupts gamma oscillations. The study utilized 18-month-old male C57BL/6 J mice and established a PND model through exploratory laparotomy. The results of both Contextual Fear Conditioning (CFC) and Morris Water Maze (MWM) experiments demonstrated that exploratory laparotomy could lead to hippocampus-dependent neurocognitive dysfunction in aged mice. We observed that exploratory laparotomy induced the transformation of microglia in the hippocampus of aged mice into an activated phenotype characterized by enlarged cell bodies and shortened processes. This transformation was accompanied by a significant increase in the expression levels of pro-inflammatory factors in hippocampal tissue, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Specific depletion of microglia in aged mice, achieved by drinking water supplemented with the colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 for seven consecutive days, resulted in a reduction of postoperative hippocampal neuroinflammation and a significant improvement in cognitive dysfunction. Similarly, perioperative inhibition of microglial activation with minocycline resulted in cognitive improvement. Additionally, we found that the expression levels of hippocampal parvalbumin (PV) and glutamate decarboxylase 67 (GAD67) were significantly reduced following exploratory laparotomy, which was accompanied by disturbed gamma oscillations. Depletion of microglia restored the expression levels of PV and GAD67 and significantly improved the disturbances in gamma oscillations. These findings suggest that the activation of hippocampal microglia and the associated neuroinflammatory response following surgery play a crucial role in PND. The underlying mechanism may be related to disturbed gamma oscillations and a reduction in the inhibitory function of PV interneurons.
    Keywords:  Gamma oscillations; Microglia; Neuroinflammation; Parvalbumin (PV); Perioperative Neurocognitive Disorders (PND)
    DOI:  https://doi.org/10.1007/s12031-025-02380-1
  25. ASN Neuro. 2025 ;17(1): 2542998
    Dysregulated Expression of Inflammasome and Extracellular Matrix Genes in C9orf72-ALS/FTD Microglia.
    Louise Thiry, Nisha S Pulimood, Ye Man Tang, Stefano Stifani.
      Hexanucleotide repeat expansion (HRE) in the non-coding region of the gene C9orf72 is the most prevalent mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 HRE contributes to neuron degeneration in ALS/FTD through both cell-autonomous mechanisms and non-cell autonomous disease processes involving glial cells such as microglia. The molecular mechanisms underlying the contribution of C9orf72-HRE microglia to neuron death in ALS/FTD remain to be fully elucidated. In this study, we generated microglia from human C9orf72-HRE and isogenic iPSCs using three different microglia derivation methods. RNA sequencing analysis reveals a cell-autonomous dysregulation of extracellular matrix (ECM) genes and genes involved in pathways underlying inflammasome activation in C9orf72-HRE microglia. In agreement with elevated expression of inflammasome components, conditioned media from C9orf72-HRE microglia enhance the death of C9orf72-HRE motor neurons implicating microglia-secreted molecules in non-cell autonomous mechanisms of C9orf72 HRE pathology. These findings suggest that aberrant activation of inflammasome-mediated mechanisms in C9orf72-HRE microglia results in a pro-inflammatory phenotype that contributes to non-cell autonomous mechanisms of motor neuron degeneration in ALS/FTD.
    Keywords:  Amyotrophic lateral sclerosis; C9orf72; RNA sequencing; extracellular matrix; inflammasome; microglia
    DOI:  https://doi.org/10.1080/17590914.2025.2542998
  26. J Biomed Res. 2025 Aug 25. 1-14
    HDGF derived from Müller cells enhances the activation of microglia in diabetic retinopathy.
    Aowang Qiu, Wenjie Yin, Ningyu Wang, Xin Wang, Qinghuai Liu, Weiwei Zhang.
      Diabetic retinopathy (DR), a common complication of diabetes, is characterized by retinal angiogenesis and inflammation. The role of hepatoma-derived growth factor (HDGF) in mediating inflammation during DR remains unclear. We measured HDGF levels in aqueous humor and found that HDGF increased in DR but decreased after anti-angiogenesis treatment. Using public single-cell RNA sequencing datasets, we found that elevated HDGF in DR was mainly produced by Müller cells and targeted microglia. Additionally, integrin beta 2 ( Itgb2), a target gene of HDGF that induces microglial activation, was significantly upregulated in DR. To verify these results, we performed ELISA, qPCR, western blot, and fluorescence immunostaining in cultured Müller and microglial cells treated with HDGF or anti-HDGF, as well as in DR mice receiving intravitreal injections of HDGF or its antibody. Exogenous HDGF further promoted microglial activation, migration, and secretion of pro-inflammatory cytokines, while neutralizing HDGF suppressed these effects caused by high glucose. Furthermore, the HDGF receptor nucleolin (NCL) was overexpressed in microglia under high glucose stimulation. Therefore, blocking HDGF from Müller cells in DR reduced the excessive inflammatory response of microglia, highlighting HDGF as a potential therapeutic target.
    Keywords:  Müller cell; diabetic retinopathy; hepatoma-derived growth factor; inflammatory response; integrin beta 2; microglia
    DOI:  https://doi.org/10.7555/JBR.38.20240386
  27. Front Biosci (Landmark Ed). 2025 Jun 30. 30(7): 39311
    HCAR2 Exerts Anti-Depressive Effects on Corticosterone-Induced Depression in Mice by Modulating Microglial Activity.
    Zhao Pan, Li Jiang, Jiacheng Chen, Sicong Xu, Ping Zhang, Yili Yi, Yangzhi Xie, Yongjun Chen.
       BACKGROUND: The metabolites derived from judicious dietary choices play a crucial role in the management and treatment of depression. Hydroxy-carboxylic acid receptor 2 (HCAR2) functions as a receptor for various diet-derived metabolites. Although a growing body of evidence indicates these metabolites exert beneficial effects on depression, the precise mechanisms underlying these benefits require further investigation.
    METHODS: We established a mouse model of corticosterone (Cor)-induced depression to evaluate the therapeutic potential of HCAR2 activation on depression. A series of behavioral experiments were conducted to investigate whether HCAR2 activation could alleviate depressive-like behaviors in mice. The neuroprotective effects of HCAR2 in the hippocampus were examined using Nissl and hematoxylin-eosin (HE) staining. The levels of monoamine neurotransmitters in mouse serum were quantified, as well as the cell viability and lactate dehydrogenase (LDH) activity of hippocampal neurons co-cultured with primary microglia. Microglia-associated neuroinflammation was evaluated by quantifying pro-inflammatory cytokines using ELISA, and by assessing the polarization state of M1 microglia, including the mRNA expression levels of M1 markers and double fluorescence staining for inducible nitric oxide synthase/ionized calcium-binding adapter molecule 1 (iNOS/Iba1). The expression level of proteins in the protein kinase B-inhibitor of nuclear factor kappa-B kinase subunits alpha and beta-nuclear factor kappa-light-chain-enhancer of activated B cells (AKT-IKKαβ-NFκB) pathway in primary microglia was analyzed using western blot. Transcriptomic changes in microglia induced by HCAR2 activation were examined through RNA sequencing. Mice were fed PLX5622 chow to deplete microglia in vivo.
    RESULTS: Activation of HCAR2 by its agonist MK-6892 in a Cor-induced model of depression significantly alleviated depressive-like behaviors, attenuated hippocampal neuronal injury, increased serum monoamine levels, reduced microglia-associated neuroinflammation, and inhibited the expression of proteins in the AKT-IKKαβ-NFκB pathway in primary microglia. Additionally, HCAR2 activation markedly enhanced hippocampal neuronal viability and decreased LDH activity in this co-culture system. Importantly, these protective effects were abolished in HCAR2 knockout mice. RNA sequencing revealed that HCAR2 activation induced changes in multiple signaling pathways. Moreover, the depletion of microglia also eliminated the protective effects of MK-6892.
    CONCLUSION: Activation of HCAR2 can reduce depressive-like behaviors, neuronal injury, and neuroinflammation. Our findings suggest these neuroprotective effects are, at least in part, mediated through modulation of microglial activity by HCAR2.
    Keywords:  HCAR2; depression; microglia; neuroinflammation
    DOI:  https://doi.org/10.31083/FBL39311
  28. Nat Neurosci. 2025 Aug;28(8): 1577
    Swapping microglia to treat ALSP.
    Rebecca Wright.
      
    DOI:  https://doi.org/10.1038/s41593-025-02047-5
  29. Alcohol Clin Exp Res (Hoboken). 2025 Aug 04.
    Alcohol consumption in P301S mice accelerates gait impairments, modifies aggregation of pathological tau and alters microglia within the hippocampus.
    Nicole M Maphis, Dominic A Furlano, Seth A David, David N Linsenbardt.
       BACKGROUND: Excessive alcohol use has emerged as the strongest modifiable risk factor for the development of Alzheimer's disease (AD), but the underlying neural mechanisms are only beginning to be understood. Recent preclinical work suggests that alcohol consumption may have an impact on many pathologies and phenomena crucial to the development and pathogenesis of AD. However, little attention has been focused on pure tauopathy models to closely examine tau pathogenesis and neuroinflammation within a voluntary alcohol exposure paradigm.
    METHODS: We exposed a mouse model of pathological tau (pTau), P301S, to a voluntary alcohol paradigm known as drinking-in-the-dark (DID) for 21 days of voluntary daily alcohol consumption.
    RESULTS: In P301S mice, moderate alcohol consumption contributed to gait disruptions, acceleration of pTau spread, and enhancement of damage-associated microglia.
    CONCLUSIONS: This work identifies key interactions between alcohol and AD-related phenotypes which set the stage for future investigation into the neurobiological mechanisms behind these interactions.
    Keywords:  Alzheimer's disease; alcohol; gait; neuroinflammation; pathological tau
    DOI:  https://doi.org/10.1111/acer.70123
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