bims-microg 2026-09-27 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–09–27
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Stroke drives glioma progression through the emergence of tumor-associated astrocytes with reduced Ca2+ activity.
Compartmentalized B cell-microglia crosstalk drives ischemic white matter demyelination.
Aberrant phase separation from a rare ABI3 mutation drives microglial dysfunction and Alzheimer's risk.
Distinct single-nucleus RNA-seq changes among non-neuronal cells in ADNC, LATE-NC, and mixed pathologies.
α1-Antitrypsin attenuates microglial NLR family pyrin domain containing 3 inflammasome activation via cannabinoid receptor 2 signaling to ameliorate α-synucleinopathy-related behavioral deficits.
TMEM59 regulates microglial Aβ phagocytosis in a TREM2-dependent manner and acts as a potential therapeutic target for Aβ amyloidosis.
Hippocampal AdipoR1 regulates the microglial response and delays disease progression in a mouse model of Alzheimer's disease.
Myeloid deficiency of RORα exacerbates lipid dysregulation and laser-induced choroidal neovascularization.
Compartment-specific inhibition of cytosolic Cathepsin B mitigates microglial senescence in the aging brain.
CX3CL1-CX3CR1 signaling shapes the sex- and region-dependent neuroimmune response to LPS: Impact on plasticity and kynurenine pathway metabolism in the hippocampus.
Caspase-3 regulates RNA splicing and mitochondrial dynamics in microglia during Parkinson's disease.
Topoisomerase I inhibition yields a CD74high/MHChigh human microglial subtype with enhanced Aβ uptake.
Porphyromonas gingivalis Promotes Lipid Droplet-Mediated Microglial Dysfunction.
Photoreceptor outer segments promote the accumulation of lipid droplets in microglia by reprogramming lipid metabolism.
IFN-γ-Responsive Microglia-Derived Extracellular Vesicles Impair White Matter Repair After Stroke Through a miR-9-5p/NEDD4-Dependent Mechanism.
Challenges in Developing a Microglial NF-Kappa B Conditional Mouse Model for Glioblastoma Studies.
Elevated ISG15 reinforces RIG-I/MDA5-linked macrophage-microglia crosstalk during blood-brain barrier disruption in neuromyelitis optica spectrum disorder.
JQ-1 attenuates microglial activation and retinal pathology in experimental diabetic retinopathy with modulation of Pagr1a/JAK2/STAT3 signaling.
Inhibition of STING Protects the Neuroretina in an Ndufs4 Knockout Mouse Model of Mitochondrial Complex 1 Deficiency.
Developmental synchrony of retinal waves, apoptosis, and angiogenesis in postnatal retina.

Nat Cancer. 2026 Sep 25.

Stroke drives glioma progression through the emergence of tumor-associated astrocytes with reduced Ca2+ activity.

Qi Ye, Christine Madamba, Junsung Woo, Tiffany J Choy, Kate F Wheeler, Jiangshan Zhan, Carlo D Cristobal, Catalina Spjut, Donghui Shin, Juyeon Jo, Roshan R Ailani, Joshua Smith, Khatri Latha, Akdes Serin Harmanci, Hari Krishna Yalamanchili, Marco Gallo, Kyuson Yun, Yana K Reshetnyak, Eunhee Kim, Yongsoo Kim, Ganesh Rao, Benjamin Deneen, Hyun Kyoung Lee.

Epidemiological studies suggest that persons with a history of stroke are at increased risk of developing brain tumors, yet the mechanisms linking brain injury to glioma progression remain unclear. Here we show that stroke promotes tumor infiltration into injured brain regions in human and mouse glioma models, accompanied by reduced overall survival. Stroke induces remodeling of the tumor microenvironment, including the emergence of a distinct population of tumor-associated astrocytes (TAAs) with diminished Ca2+ activity at the invasive front and enrichment of tumor-associated microglia and macrophages (TAMs). Restoring TAA Ca2+ signaling or TAM depletion suppresses stroke-induced glioma progression, identifying both populations as critical mediators of the injury response. Mechanistically, we identified SLC4A4 as a key regulator of Ca2+ activity in TAAs and CCL2-mediated TAM recruitment. Collectively, our findings establish stroke-induced remodeling of astrocytic Ca2+ signaling and TAMs as drivers of glioma progression and link brain injury to malignant disease.

DOI: https://doi.org/10.1038/s43018-026-01238-8
Nat Commun. 2026 Aug 24. pii: 10115. [Epub ahead of print]17(1):

Compartmentalized B cell-microglia crosstalk drives ischemic white matter demyelination.

Lulu Xu, Sheng Yang, Lifang Zhu, Zhicheng Mei, Wanning Li, Yunhui Chu, Xiaowei Pang, Hang Zhang, Shuhan Lu, Lian Chen, Jiayi He, Menglu Tian, Yuxin Liu, Luoqi Zhou, Ke Shang, Jun Xiao, Wei Wang, Daishi Tian, Chuan Qin.

Ischemic white matter injury and the consequent neuroimmune response can contribute to vascular cognitive impairment. The role of B cells in ischemic white matter injury is unclear. Here, we show that crosstalk between meningeal B cells and CNS-resident microglia exacerbates white matter injury and vascular cognitive impairment. The B cell population expands and is activated in the dura mater, correlating with worsened white matter damage and neuroinflammation, whereas B cell depletion alleviates myelin thinning and cognitive impairment following chronic cerebral hypoperfusion in adult male mice. Mechanistically, microglia recruit meningeal B cells via MIF-CD74/CXCR4 signaling, and B cells adopt an IgG-secreting phenotype. IgG-secreting B cells induce microglial ferroptosis through Fc gamma receptors. Our data show that B cells contribute to white matter injury and cognitive impairment.

DOI: https://doi.org/10.1038/s41467-026-76817-5
Alzheimers Dement. 2026 Sep;22(9): e71812

Aberrant phase separation from a rare ABI3 mutation drives microglial dysfunction and Alzheimer's risk.

Shengnan Li, Jiongtong Lu, Kaixing Zeng, Xingyu Lu, Jiahao Zhang, Sifan Feng, Chunmei Liang, Yujie Cai, Shi Yao, Qing Huang, Guocong Liang, Rui Chen, Li Li, Fubin Ma, Jiawei Xing, Chaoyue Ouyang, Lv Luo, Jiaying Wang, You Li, Shengbo He, Yuanyuan Zhao, Yan Wang, Lili Cui.

   INTRODUCTION: Although the ABI3 S209F variant is a recognized genetic risk for Alzheimer's disease (AD), its pathogenic mechanism remains elusive.
METHODS: Using AD mouse models (amyloid precursor protein/presenilin 1 [APP/PS1] transgenic mice, 5×familial Alzheimer's disease (5×FAD) transgenic mice) with microglia-specific knockdown of Abelson-interactor family member 3 (ABI3) or expression of the wild-type or S209F mutant, we assessed disease pathology. Primary mouse microglia and HMC3 cells were used to examine ABI3 function and S209F effects. Liquid-liquid phase separation (LLPS) properties were characterized in cellular systems and with recombinant proteins.
RESULTS: ABI3 was highly expressed in AD microglia. ABI3 enhanced microglial clustering around amyloid beta (Aβ) plaques, promoted Aβ clearance, and ameliorated cognitive decline, whereas S209F abolished these effects. Mechanistically, ABI3 undergoes LLPS essential for microglial migration and phagocytosis. The S209 residue lies within an intrinsic disordered region, and S209F disrupts phosphorylation-dependent LLPS, thereby impairing microglial functions.
DISCUSSION: The AD-associated ABI3 S209F variant drives pathogenesis by disrupting LLPS, causing microglial dysfunction. Enhancing ABI3 phase separation represents a potential therapeutic strategy to boost microglial activity against Aβ pathology.

Keywords:  Abelson‐interactor family member 3; Alzheimer's disease; amyloid beta; liquid–liquid phase separation; microglia

DOI:  https://doi.org/10.1002/alz.71812
Alzheimers Dement. 2026 Sep;22(9): e71810

Distinct single-nucleus RNA-seq changes among non-neuronal cells in ADNC, LATE-NC, and mixed pathologies.

Qi Qiao, Yuriko Katsumata, Hsin-Yu Lai, Kevin Z Lin, Steven A Claas, Mariano I Gabitto, Josh M Morganti, Peter T Nelson, Shubhabrata Mukherjee, David W Fardo.

   INTRODUCTION: Limbic-predominant age-related transactive response DNA binding protein 43 kDa encephalopathy neuropathological change (LATE-NC) frequently co-occurs with Alzheimer's disease neuropathologic change (ADNC), complicating classification. Cell type-specific molecular features distinguishing LATE-NC-dominant, ADNC-dominant, and mixed LATE-NC and ADNC pathology remain incompletely characterized.
METHODS: We analyzed single-nucleus RNA sequencing data from the Seattle Alzheimer's Disease Brain Cell Atlas consortium, focusing on non-neuronal cells in the middle temporal gyrus (MTG). Donors were stratified into LATE-NC dominant, ADNC dominant, and mixed LATE-NC and ADNC. Differential expression and gene set enrichment analyses were performed across glial and vascular cell supertypes.
RESULTS: Distinct transcriptional patterns differentiated pathologies. Astrocytes, microglia, and oligodendrocytes exhibited differential expression between LATE-NC- and ADNC-dominant cases. Representative genes and pathways highlighted these distinctions, with LATE-NC dominant showing enrichment in signaling and RNA regulation, ADNC dominant in mitochondrial dysfunction, and mixed pathology in translational dysregulation and lipid remodeling, suggesting a distinct biological state.
DISCUSSION: Findings highlight biological heterogeneity and non-neuronal molecular features relevant to disease classification and future research.
CLINICAL TRIAL REGISTRATION INFORMATION: Not applicable. This study is a secondary analysis of publicly available Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) data.

Keywords:  Alzheimer's disease; aging brain; comorbid neuropathology; differential gene expression; glial cell types; limbic‐predominant age‐related transactive response DNA binding protein 43 kDa encephalopathy; single‐nucleus RNA sequencing; transcriptomics

DOI:  https://doi.org/10.1002/alz.71810
Mol Biomed. 2026 Sep 20. pii: 180. [Epub ahead of print]7(1):

α1-Antitrypsin attenuates microglial NLR family pyrin domain containing 3 inflammasome activation via cannabinoid receptor 2 signaling to ameliorate α-synucleinopathy-related behavioral deficits.

Linjuan Feng, Hsuan Lo, Weipin Weng, Jiahao Zheng, Yixin Sun, Wei Lin, Xiaochun Chen, Yanping Wang, Xiaodong Pan.

  α-Synucleinopathies are marked by persistent neuroinflammation and disabling non-motor symptoms involving nucleus accumbens (NAc) dysfunction, yet the neuroimmune mechanisms linking microglial activation to accumbal synaptic pathology remain poorly understood. Here, we identify α1-antitrypsin (AAT) as a previously unrecognized modulator of cannabinoid receptor 2 (CB2R)-associated signaling in α-syn pathology. An acute transcriptomic screen revealed prominent induction of the Serpina1 gene family, while primary-microglial and chronic AAV-α-syn experiments showed that Cnr2 deficiency amplified Serpina1/AAT responses, consistent with an insufficient compensatory reaction to persistent inflammation. Molecular docking, reciprocal co-immunoprecipitation, and surface plasmon resonance provided complementary evidence supporting an AAT-CB2R association under the respective assay conditions. Functionally, AAT reduced the α-syn-associated elevation of intracellular cAMP in an AM630-sensitive manner and attenuated ATP-evoked Ca2⁺ responses, calpain-1 activity, GSK-3β N-terminal cleavage, and NLRP3/caspase-1-related cytokine production; these effects were substantially diminished in Cnr2-deficient microglia. Calpeptin reproduced key molecular effects, implicating calpain-related proteolysis in this neuroimmune response. In vivo, intracerebroventricular AAT preserved NAc synaptic ultrastructure, ameliorated excitatory synaptic abnormalities in dopamine D2 receptor-expressing medium spiny neurons, and improved fear-memory retrieval, spontaneous alternation, and anxiety-like behavior, without affecting novel object recognition or motor performance. Several effects were attenuated under Cnr2-deficient conditions, although selected electrophysiological responses persisted. Our findings identify AAT-CB2R-linked signaling as a modulator of microglial inflammatory homeostasis and support the therapeutic potential of AAT for NLRP3-associated neuroinflammation and non-motor dysfunction in α-synucleinopathies.

Keywords:  Cannabinoid receptor 2 (CB2R); Dopamine receptor type 2-expressing medium spiny neurons (D2-MSNs); Microglial NLRP3 inflammasome; Nucleus accumbens (NAc); α-Synucleinopathies; α1-Antitrypsin (AAT)

DOI:  https://doi.org/10.1186/s43556-026-00583-5
Alzheimers Dement. 2026 Sep;22(9): e71873

TMEM59 regulates microglial Aβ phagocytosis in a TREM2-dependent manner and acts as a potential therapeutic target for Aβ amyloidosis.

Jian Meng, Yong Wang, Jinghui Wang, Yiqing Chen, Zihao Zhao, Ziqian Tang, Jing Cao, Xian Zhang, Hong Luo, Huihui Li, Yili Wu, Yingjun Zhao, Weihong Song, Yun-Wu Zhang.

   INTRODUCTION: Microglia-mediated clearance of amyloid beta (Aβ) is crucial for mitigating Alzheimer's disease (AD) progression, yet the molecular regulators of microglial phagocytosis remain incompletely understood.
METHODS: We assessed AD-related phenotypes in 5xFAD mice with microglia-specific deletion of transmembrane protein 59 (TMEM59). Microglial transcriptomic profiling was performed using single-cell RNA sequencing (scRNA-seq). A chaperone-mediated autophagy-targeting chimera (CMATAC) peptide was developed to degrade TMEM59, and its therapeutic efficacy was evaluated.
RESULTS: Microglia-specific TMEM59 ablation attenuated cognitive deficits, Aβ plaque burden, and synapse loss in 5xFAD mice. TMEM59 deficiency reprogrammed disease-associated microglia toward a highly phagocytic state. Mechanistically, TMEM59 deficiency enhanced microglial Aβ phagocytosis in a triggering receptor expressed on myeloid cells 2 (TREM2)-dependent manner, as it stabilized TREM2 protein, whereas loss of TREM2 abolished these protective effects. Treatment with the TMEM59-degrading CMATAC peptide alleviated behavioral deficits and enhanced microglial Aβ phagocytosis in 5xFAD mice.
DISCUSSION: TMEM59 is a key regulator of microglial phagocytosis in AD and a novel target for amyloidosis intervention.

Keywords:  Alzheimer's disease; TMEM59; TREM2; amyloid; chaperone‐mediated autophagy‐targeting chimera; microglia; phagocytosis; transmembrane protein 59; triggering receptor expressed on myeloid cells 2

DOI:  https://doi.org/10.1002/alz.71873
Mol Psychiatry. 2026 Sep 23.

Hippocampal AdipoR1 regulates the microglial response and delays disease progression in a mouse model of Alzheimer's disease.

Jing Li, Lin Jiang, Fenglei Chao, Lei Zhang, Chunnian Hu, Yuning Zhou, Shun Wang, Qing Pan, Yanmin Luo, Jing Tang, Xin Liang, Yue Li, Peilin Zhu, Yuhui Deng, Shan Liu, Yingqiang Qi, Qian Xiao, Yong Tang, Chunni Zhou.

Adiponectin, a key regulator of peripheral lipid metabolism, exhibits a positive correlation between its reduced peripheral and central levels and cognitive function in Alzheimer's disease (AD). Previous studies suggest that adiponectin primarily crosses the blood-brain barrier to exert its neuroprotective and anti-inflammatory effects within the brain. However, the detailed mechanisms through which adiponectin improves cognitive function in AD remain unclear. This study found that APP/PS1 mice exhibited cognitive impairment accompanied by decreased peripheral adiponectin levels and reduced adiponectin receptor 1 (AdipoR1) expression in the hippocampus (with no change in AdipoR2 expression). Knockdown of AdipoR1 in the hippocampus induced cognitive impairment and neuroinflammation in C57BL/6 J mice. Overexpression of AdipoR1 improved cognitive function, suppressed microglial activation and expression of inflammatory factors, promoted β-amyloid (Aβ) clearance, and inhibited excessive synaptic phagocytosis by microglia in AD model mice. In vitro and in vivo experiments revealed that AdipoR1 may regulate the activation and function of hippocampal microglia in AD by modulating their autophagy to reduce abnormal lipid droplet (LD) accumulation. This study demonstrates that AdipoR1 is a highly promising therapeutic target for restoring lipid homeostasis in AD microglia, coordinating the regulation of their phagocytic function, and delaying disease progression.

DOI: https://doi.org/10.1038/s41380-026-03907-7
Angiogenesis. 2026 Sep 25. pii: 73. [Epub ahead of print]29(4):

Myeloid deficiency of RORα exacerbates lipid dysregulation and laser-induced choroidal neovascularization.

Neetu Kushwah, Chi-Hsiu Liu, Kiran Bora, Meenakshi Maurya, Madeline C Pavlovich, Zhongjie Fu, Theodore M Kamenecka, Ye Sun, Laura A Solt, Jing Chen.

  Dysregulated lipid and cholesterol metabolism is implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of vision loss. Retinoic acid receptor-related orphan receptor alpha (RORα) is a lipid-sensing nuclear receptor genetically associated with neovascular AMD. We investigated the role of RORα in regulating AMD-like pathologies and laser-induced choroidal neovascularization (CNV) through mediating myeloid cell lipid homeostasis and function. Both systemic (Rorasg/sg) and myeloid-specific (Rorafl/fl;LysMCre) RORα deficient mice exhibited fundus lesions with aging, and exacerbated CNV with chronic subretinal inflammation, with subretinal accumulation of lipid-laden activated microglia/macrophages, and increased levels of pro-inflammatory cytokines. RORα-deficient macrophages showed enhanced lipid droplet formation and upregulation of peroxisome proliferator-activated receptor gamma (PPARγ), a lipogenic RORα target gene. Pharmacological inhibition of RORα in cultured macrophage recapitulated the effects of RORα deficiency on lipid enrichment and inflammation, whereas PPARγ inhibition in RORα deficient mice partially reversed the effects on laser-induced CNV, lipid accumulation and inflammation. Additionally, migratory chemokine receptors, including CX3CR1 and CD47, were downregulated in RORα-deficient myeloid cells, contributing to impaired elimination of inflammatory cells from the subretinal space. These findings identify RORα as a critical transcriptional regulator that links lipid dysregulation to persistent subretinal inflammation and pathological CNV highly relevant in AMD.

Keywords:  AMD; Aging; CNV; Inflammation; Lipid accumulation; Macrophages; Microglia; RORα

DOI:  https://doi.org/10.1007/s10456-026-10092-2
Pharmacol Res. 2026 Sep 20. pii: S1043-6618(26)00393-2. [Epub ahead of print]233 108478

Compartment-specific inhibition of cytosolic Cathepsin B mitigates microglial senescence in the aging brain.

Simeng Zhang, Chen Zhang, Jian Mao, Junjun Ni.

  Microglial senescence is a hallmark of brain aging, but how lysosomal dysfunction fuels their pro-aging activity remains unresolved. Here we identify cytosolic Cathepsin B (CatB) as a pivotal driver of microglial senescence. In aged mice and senescence-induced models, lysosomal membrane permeabilization releases CatB into the cytosol, where it remains enzymatically active at neutral pH. Cytosolic CatB promotes senescence, and its inhibition mitigates this process, whereas cytosolic delivery of recombinant CatB accelerates it. Mechanistically, cytosolic CatB binds and degrades small nuclear ribonucleoprotein polypeptide E (SNRPE), a spliceosome component, inducing senescence-associated phenotypes without triggering cell death. Notably, conventional CatB inhibitors active under acidic conditions are ineffective, while neutral pH-active inhibitors block microglial senescence both in vitro and in aged mouse brains. These findings uncover cytosolic CatB as a spliceosome-targeting mediator of microglial senescence and suggest SNRPE stabilization or compartment-specific CatB inhibition as potential therapeutic strategies to counter brain aging and neurodegeneration.

Keywords:  CatB; Cytosol; Lysosome; Microglia and senescence; SNRPE

DOI:  https://doi.org/10.1016/j.phrs.2026.108478
Brain Behav Immun. 2026 Sep 22. pii: S0889-1591(26)00773-7. [Epub ahead of print] 107025

CX3CL1-CX3CR1 signaling shapes the sex- and region-dependent neuroimmune response to LPS: Impact on plasticity and kynurenine pathway metabolism in the hippocampus.

Eleonora De Felice, Giovanni Signorini, Laura Bertarini, Miriam Ciani, Giovanna Rigillo, Cristina Benatti, Antonietta Vilella, Fabio Tascedda, Cristina Limatola, Federica Pellati, Laura Maggi, Silvia Alboni.

   BACKGROUND: Fractalkine signaling is a central mediator of neuron-microglia communication. We previously demonstrated that, under physiological conditions, the fractalkine receptor (CX3CR1) differentially modulates synaptic plasticity along the dorsoventral axis of the hippocampus in male but not in female mice. During systemic inflammation, CX3CR1 deficiency has been associated with altered regulation of the kynurenine pathway (KP), a metabolic route whose neuromodulatory metabolites show sex-dependent differences. However, it remains unclear how acute systemic inflammation affects synaptic plasticity and KP metabolism in the dorsal (DH) and ventral hippocampus (VH), whether these responses differ between sexes, and to what extent they depend on CX3CR1.
METHODS: Acute systemic inflammation was induced via intraperitoneal injection of lipopolysaccharide (LPS) in male and female C57BL/6J and Cx3cr1-/- mice. Long-term potentiation (LTP) was assessed at 3 and 24 h post LPS treatment in DH and VH slices using extracellular field recordings. KP metabolites were quantified at 24 h by HPLC-ESI-MS/MS.
RESULTS: In C57BL/6J males, LPS elicited a time- and region-specific modulation of plasticity, with early LTP suppression in the DH and delayed enhancement in the VH, accompanied by robust KP activation. In Cx3cr1-/- males, the KP activation and the dorsoventral pattern were altered, indicating that CX3CR1 is required for coordinated hippocampal neuroimmune responses during inflammation. In C57BL/6J females, LPS induced a modest enhancement of VH LTP together with a comparatively attenuated KP response, whereas Cx3cr1-/- females showed selective VH LTP impairment and reduced KP activation, suggesting that CX3CR1 signaling preserves VH plasticity during inflammatory challenge in females.
CONCLUSIONS: Together, our findings identify fractalkine signaling as a key modulator of hippocampal synaptic plasticity and neuroimmune-metabolic responses to inflammation in a sex- and region-dependent manner.

Keywords:  Cx3cr1; Dorsal hippocampus; Fractalkinesignaling; Kynurenine pathway; Metabolomics; Microglia; Neuroinflammation; Sex differences; Ventral hippocampus

DOI:  https://doi.org/10.1016/j.bbi.2026.107025
Cell Death Dis. 2026 Aug 04. pii: 834. [Epub ahead of print]17(1):

Caspase-3 regulates RNA splicing and mitochondrial dynamics in microglia during Parkinson's disease.

Rafael Medina-Guzmán, Bazhena Bahatyrevich-Kharitonik, Marie-Kim St-Pierre, Sara Márquez-Pérez, Elena Gavilán, Cristóbal Coronel-Guisado, Alicia Flores-Cortes, Rodrigo García-Valiente, Sandro Argüelles, Edel Kavanagh, Yiyi Yang, Tomas Deierborg, José Luis Venero, Cristina González-Aguilera, Bertrand Joseph, Miguel Ángel Burguillos.

Caspase-3, a cysteine-aspartic protease canonically known for its role in apoptotic cell death, has been implicated in several non-apoptotic functions, particularly in microglia, the brain-resident macrophages. These novel functions appear to depend on distinct levels of caspase-3 activation; however, the role of basal caspase-3 activity remains unclear. Here, we show that basal caspase-3 regulates RNA splicing in microglia, and its deficiency in a Parkinson´s disease (PD) model leads to splicing dysregulation. Loss of basal caspase-3 activity also increases double-stranded RNA (dsRNA) accumulation, inducing a type I interferon response. Additionally, caspase-3 deficiency impairs mitochondrial respiration, reduces ATP production, and causes sex-specific mitochondrial abnormalities, predominantly in female microglia. Together, our findings uncover a non-apoptotic, homeostatic role for basal caspase-3 activity in microglia. Its disruption, such as in PD, may drive key molecular features of neuroinflammation and neurodegeneration, positioning caspase-3 as a critical regulator of microglial function in health and disease.

DOI: https://doi.org/10.1038/s41419-026-09141-x
Cell Rep. 2026 Sep 23. pii: S2211-1247(26)01109-5. [Epub ahead of print]45(10): 118031

Topoisomerase I inhibition yields a CD74high/MHChigh human microglial subtype with enhanced Aβ uptake.

Verena Haage, John F Tuddenham, Natacha Comandante-Lou, Alex R Bautista, Anna S Monzel, Frankie G Garcia, Rebecca Chiu, Masashi Fujita, Prabesh Bhattarai, Charles C White, Ronak Patel, Alice Buonfiglioli, Juan Idiarte, Mathieu Herman, Alison Rinderspacher, Angeliki Mela, Wenting Zhao, Michael G Argenziano, Julia L Furnari, Matei A Banu, Donald W Landry, Jeffrey N Bruce, Peter Canoll, Ya Zhang, Tal Nuriel, Andrew A Sproul, Lotje D de Witte, Peter A Sims, Vilas Menon, Caghan Kizil, Martin Picard, Philip L De Jager.

  While efforts to identify microglial subtypes have recently accelerated, the relation of transcriptomically defined states to cellular function has been largely limited to in silico annotations. Here, we characterize two topoisomerase I inhibitors that polarize human microglia toward a distinct state characterized by increased antigen presentation gene expression. Using HMC3 cells, iPSC-derived microglia, and cerebral organoids, we show that Camptothecin induces a CD74high/MHChigh microglia-like cell subtype specialized in amyloid beta phagocytosis and reduced IL-6, IL-8, and MCP-1 secretion in response to TNF-α stimulation. Moreover, Camptothecin suppresses amyloid toxicity and restores microglia to their homeostatic morphology in a zebrafish amyloid proteinopathy model. We also identify Topotecan, a Food and Drug Administration (FDA)-approved Camptothecin analog, as a driver of the CD74high/MHChigh signature. This report provides a reproducible approach to recapitulate a human microglial state in vitro, enabling its functional characterization and providing a foundation for rational modulation of human microglia in vivo.

Keywords:  CP: neuroscience; human microglia; in silico drug screening; in vitro models for human microglial subtypes; microglia subtypes; mitochondrial phenotyping; single cell

DOI:  https://doi.org/10.1016/j.celrep.2026.118031
J Dent Res. 2026 Sep 24. 220345261478558

Porphyromonas gingivalis Promotes Lipid Droplet-Mediated Microglial Dysfunction.

M S Riaz Rajoka, K N Valladares, C L Prairie, W Li, P King, J Katz, S M Michalek, P Zhang.

  Growing evidence supports a strong association between periodontitis and Alzheimer's disease (AD), yet the mechanisms linking these conditions remain poorly defined. In neurodegenerative disorders, including AD, microglia are often characterized by increased accumulation of lipid droplets (LD), heightened activation, and impaired function. In this study, we examined whether Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, promotes LD accumulation in microglia and disrupts their function. We found that infection with Pg (ATCC 33277) induces robust LD accumulation in BV2 microglial cells and in microglia from Pg-infected App knock-in mice. This Pg-driven LD buildup was closely associated with elevated reactive oxygen species (ROS) production, impaired phagocytic ability, and altered activation. Notably, pharmacologic inhibition of LD with a long-chain fatty acyl-CoA synthetase inhibitor effectively reversed Pg-induced LD accumulation, mitigated ROS production, and restored phagocytic function, thus underscoring the critical role of lipid metabolism in regulating microglial function. These findings support a model in which, in the context of periodontitis, systemic dissemination of periodontal pathogens and inflammatory mediators promotes LD accumulation in microglia, and this metabolic alteration exacerbates microglia dysfunction via a self-reinforcing cycle of excessive oxidative stress and impaired phagocytosis, potentially accelerating AD progression.

Keywords:  Alzheimer’s disease; lipid metabolism; neuroinflammation; oxidative stress; periodontitis; phagocytosis

DOI:  https://doi.org/10.1177/00220345261478558
Front Immunol. 2026 ;17 1892763

Photoreceptor outer segments promote the accumulation of lipid droplets in microglia by reprogramming lipid metabolism.

Lingling Ge, Danyang Yu, Lingyan Yan, Yingnan Lv, Ruiyao He, Ling Yuan, Ping Duan, Juncai He.

  Retinal degeneration (RD) ultimately leads to blindness owing to progressive photoreceptor loss. Previous studies have shown that microglia play a key role in photoreceptor degeneration through multiple phenotypes. However, the determinants of their phenotypic regulation remain unclear. As microglia migrate into the subretinal space and engulf photoreceptor outer segments (POSs), we aim to investigate how POSs affect microglial activation and the relevant pathways. A classic mouse microglial cell line (BV2) was used to explore the effect of POS exposure on microglia activation. Transcriptomic and lipidomic analyses were used to investigate the mechanisms by which POS treatment influenced microglial lipid metabolism. A classic RD model induced by sodium iodate (SI) was used to confirm the microglial phenotype activated by POS in vivo. Using a mouse microglial cell line (BV2), we found that POS exposure induced a novel microglial state distinguished by a distinctive morphological feature, a specific transcriptional signature, and a distinct lipidomic profile compared with the LPS and untreated groups. BV2 cells with prolonged POS exposure showed significantly different lipid metabolic pathways, particularly genes associated with cholesterol metabolism. This lipidomic analysis further identified a parallel increase in free fatty acid (FFA) and cholesterol ester (CE) levels, with FFA-22:6 (DHA) and CE-22:6 being the most upregulated, a key metabolic transition that might play a crucial role in promoting lipid droplet (LD) formation in POS-treated microglia. Consistent with these findings, LD accumulation was also observed in the microglia located in the photoreceptor layer of the SI-induced retinal degeneration model. Functionally, POS-treated microglia showed the suppression of interferon-responsive transcriptional programs and anti-inflammatory effects, and exhibited impaired engulfment capabilities while maintaining normal lysosomal function. Taken together, these findings reveal a lipid-mediated mechanism that drives microglial phenotypic switching and provide a more physiologically relevant in vivo model to mimic microglial activation in degenerative retinas than LPS stimulation.

Keywords:  cholesterol metabolism; lipid droplets; lipid-droplet-accumulating microglia; microglia; photoreceptor outer segments; retinal degeneration

DOI:  https://doi.org/10.3389/fimmu.2026.1892763
Glia. 2026 Nov;74(11): e70235

IFN-γ-Responsive Microglia-Derived Extracellular Vesicles Impair White Matter Repair After Stroke Through a miR-9-5p/NEDD4-Dependent Mechanism.

Dongliang Qian, Tongtong Xu, Yiyan Guo, Shiyu Deng, Yanqin Geng, Hanlai Li, Lin Gan, Qianyuan Lian, Jingjing Xu, Huaitong Yao, Jing Ye, Enkhbat Myagmartsend, Guo-Yuan Yang, Jixian Wang, Yaohui Tang, Qingzhu An.

Promoting white matter repair is crucial for functional recovery after ischemic stroke. Our previous study has identified an IFN-γ-responsive microglia phenotype in the brain after stroke. However, its role in white matter repair remains poorly understood. Herein, we find that extracellular vesicles derived from IFN-γ-responsive microglia (IFN-γ EVs) are internalized by oligodendrocyte precursor cells (OPCs), leading to impaired OPCs proliferation, survival, and differentiation and reduced white matter repair in a murine transient middle cerebral artery occlusion (tMCAO) model. Mechanistically, miR-9-5p enrichment in IFN-γ EVs suppresses NEDD4 expression, a key regulator of myelination, leading to reduced OPCs maturation and white matter repair. Genetic interventions including miR-9-5p knockdown in IFN-γ EVs or NEDD4 overexpression in OPCs restore remyelination and functional recovery. Our findings demonstrate that IFN-γ EVs act as negative regulators of OPCs differentiation and remyelination following ischemic stroke via miR-9-5p/NEDD4 pathway. Targeting this signaling axis may represent a novel therapeutic strategy to enhance remyelination and functional recovery after stroke.

DOI: https://doi.org/10.1002/glia.70235
Cells. 2026 Sep 16. pii: 1668. [Epub ahead of print]15(18):

Challenges in Developing a Microglial NF-Kappa B Conditional Mouse Model for Glioblastoma Studies.

Amy T Trang, Ahmet Alptekin, Michael Goodall, Surendra K Rajpurohit, Ryan Frerichs, Ashley Koch, Thaiz F Borin, Ahmet K Korkaya, Karan Soni, Ali S Arbab, Jennifer W Bradford.

  Tumor microenvironments (TME) play a crucial role in the formation, progression, and drug resistance of many cancers, including glioblastoma (GBM). Microglia are the resident innate immune cells of the central nervous system and are associated with brain cancers like GBM. However, there are limited studies about the specific effects that microglia have on GBM tumors. One possible way to reduce GBM tumor progression is by targeting key signaling pathways in microglia, such as the nuclear factor-kappa B (NF-κB) signaling pathway, which has been implicated in both microglia/macrophage phenotype polarization and in brain cancers like GBM. Therefore, this study aimed to produce a p65fl/fl/CX3CR1creER/+ mouse model, an inducible p65 knockout mouse model to be used for studying how inhibition of canonical NF-κB signaling in microglia affects GBM tumors. Following tamoxifen administration to the mouse, p65, a transcription factor of the canonical NF-κB pathway, should be deleted in microglia due to activation of a Cre recombinase (creER) under the control of the CX3CR1 promoter. This mouse model was characterized to determine whether the p65 gene was effectively deleted in microglia using this system. Our data show that tamoxifen-treated p65fl/fl/CX3CR1creER/+ mice had only partial deletion of the p65 gene, which corresponded to only slightly lower p65 expression in microglia compared to control mice. Partial p65 deletion in microglia was also observed in p65fl/fl/CX3CR1creER/+ mice that received both GBM implantations and tamoxifen treatment compared to a vehicle control group. Despite the low p65 deletion efficiency, we show that slight decreases in microglial p65 can alter gene expression of various genes involved in microglial phenotype polarization, which is exacerbated in the context of GBM. Overall, the data from this study show minimal p65 deletion in microglia from tamoxifen-treated p65fl/fl/CX3CR1creER/+ mice. The limitations of this model will serve as guidance to the GBM TME field for future animal model production.

Keywords:  NF-κB; glioblastoma; microglia

DOI:  https://doi.org/10.3390/cells15181668
Int Immunopharmacol. 2026 Sep 19. pii: S1567-5769(26)01280-4. [Epub ahead of print] 117433

Elevated ISG15 reinforces RIG-I/MDA5-linked macrophage-microglia crosstalk during blood-brain barrier disruption in neuromyelitis optica spectrum disorder.

Yunfeng Niu, Jing Sun, Yusen Han, Ruoyi Guo, Zhichao Yao, Kazuo Sugimoto, Jia Liu, Bin Li.

   BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an AQP4-IgG-mediated astrocytopathy characterized by blood-brain barrier (BBB) injury and myeloid inflammation. We investigated whether interferon-stimulated gene 15 (ISG15) contributes to myeloid activation through RIG-I-like receptor (RLR) signaling.
METHODS: Single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from patients with NMOSD was combined with validation in monocytes, serum, and cerebrospinal fluid. THP-1-derived macrophages and HMC3/BV2 microglia underwent LPS and/or IFN-β stimulation and ISG15 knockdown or overexpression. To assess macrophage-derived ISG15 effects on microglial polarization, ISG15-manipulated macrophages were non-contact cocultured with microglia in Transwell inserts, and microglial M1/M2 markers were measured. Western blotting quantified free and conjugated ISG15. ISG15-RIG-I association were examined by co-IP. An AQP4-IgG/human complement passive-transfer mouse model provided in vivo validation.
RESULTS: NMOSD PBMCs showed monocyte expansion and an ISG15-high interferon/RLR signature, with increased ISG15 in CD14+ monocytes, serum, and cerebrospinal fluid. In macrophages, LPS plus IFN-β increased inflammatory cytokines, migration, and both free/conjugated ISG15. ISG15 overexpression or knockdown bidirectionally altered macrophage and microglial phenotypes; the Transwell coculture confirmed that macrophage ISG15 status directly modulated microglial M1/M2 polarization. ISG15 modulated RIG-I/MDA5/LGP2 expression, with RIG-I overexpression partially rescuing the RLR program after knockdown. Co-IP confirmed physical association between ISG15 and RIG-I. In vivo, BBB disruption coincided with ISG15-high infiltrating and resident myeloid cells and RLR upregulation.
CONCLUSION: Elevated ISG15 following BBB injury reinforces RIG-I/MDA5/LGP2 signaling and drives macrophage-microglia inflammatory crosstalk in NMOSD, establishing the ISG15-RLR axis as a key amplification pathway that bridges peripheral and central myeloid responses.

Keywords:  Blood–brain barrier; ISG15; Neuroinflammation; Neuromyelitis optica spectrum disorder; RIG-I/MDA5; Type I interferon

DOI:  https://doi.org/10.1016/j.intimp.2026.117433
Int Immunopharmacol. 2026 Sep 23. pii: S1567-5769(26)01275-0. [Epub ahead of print]189 117428

JQ-1 attenuates microglial activation and retinal pathology in experimental diabetic retinopathy with modulation of Pagr1a/JAK2/STAT3 signaling.

Ran Wang, Liwen Wang, Xu Sun, Chao Zhang, Bingyu Wang, Qiqi Jiang, Xiang Li, Ying Zhu.

  Diabetic retinopathy (DR) is a major vision-threatening complication of diabetes mellitus, in which chronic inflammation and retinal microglial activation contribute to disease progression. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator involved in inflammatory transcription; however, the downstream mediators associated with BET inhibition in diabetic retinal inflammation remain poorly characterized. In this study, high-glucose (HG)-stimulated BV2 microglia and streptozotocin (STZ)-induced diabetic mice were used to investigate the effects and mechanisms of the BET inhibitor JQ-1. Bulk RNA sequencing identified Pagr1a as a candidate mediator of JQ-1-associated transcriptional regulation. Candidate prioritization was based on HG responsiveness, the magnitude of JQ-1-associated reversal, and baseline expression abundance. BRD4 knockdown, BRD4 overexpression, promoter reporter assays, and ChIP-qPCR were used to examine the relationship between BRD4 and Pagr1a transcription. HG exposure was associated with increased BRD4 and Pagr1a expression, enhanced BRD4 occupancy at the Pagr1a promoter, and activation of JAK2/STAT3 signaling. BRD4 knockdown or JQ-1 treatment reduced Pagr1a expression and promoter activity. Pagr1a overexpression (Pagr1a-OE) partially attenuated the inhibitory effects of JQ-1 on JAK2/STAT3 phosphorylation and microglial inflammatory responses. In STZ-induced diabetic mice, short-term JQ-1 treatment reduced retinal microglial activation, inflammatory responses, oxidative stress, apoptosis, and structural injury without markedly altering systemic metabolic parameters. Retinal Pagr1a knockdown also reduced microglial JAK2/STAT3 activation and inflammatory marker expression, whereas combined JQ-1 and Pagr1a knockdown produced comparable or greater protection than JQ-1 alone in selected endpoints. These findings support a BRD4-associated Pagr1a/JAK2/STAT3 regulatory mechanism in diabetic retinal inflammation and identify Pagr1a as a candidate therapeutic target for further investigation.

Keywords:  Diabetic retinopathy; JAK2/STAT3 signaling pathway; JQ-1; Microglia; Pagr1a

DOI:  https://doi.org/10.1016/j.intimp.2026.117428
Exp Eye Res. 2026 Sep 23. pii: S0014-4835(26)00394-5. [Epub ahead of print] 111238

Inhibition of STING Protects the Neuroretina in an Ndufs4 Knockout Mouse Model of Mitochondrial Complex 1 Deficiency.

Jong-Jer Lee, Yu-Ting Hsiao, Hsiu-Mei Huang, Mu-Chan Ke, Shih-Ting Tsao, Yao-Sheng Huang, Tsu-Kung Lin.

   PURPOSE: Ndufs4 encodes a key subunit of mitochondrial complex I, and its mutation causes NADH dehydrogenase deficiency associated with Leigh syndrome and Leber hereditary optic neuropathy. In Ndufs4 knockout (KO) mice, vision loss occurs alongside an "inflammatory wave" that disrupts neuroretinal function. In this study, we explore a novel inflammation-driven pathogenic mechanism and whether treatments targeting inflammatory pathways can mitigate neuroretina degeneration.
METHODS: Transcriptomic analysis of neuroretinal tissue from Ndufs4-KO mice identified immune-response activation as the most enriched pathway, with a twofold upregulation of stimulator of interferon genes (STING). Based on these findings, Ndufs4-KO mice received intraperitoneal injections of the STING inhibitors C-176 or SN-011 three times weekly from postnatal day 29 to 42; controls received vehicle only. Inflammatory cytokines were measured using ELISA, while retinal structure and function were evaluated through immunofluorescence and electroretinography (ERG).
RESULTS: Immunofluorescence showed infiltration of Iba1-positive microglia into inner retinal layers of Ndufs4-KO mice, which was reduced by nearly 50% following C-176 and SN-011 treatment. ELISA confirmed decreased levels of the inflammatory markers CCL5 and ICAM-1. Untreated Ndufs4 retinas exhibited thinning of the inner retinal layers to about 70% of normal, whereas treated mice retained ∼85-90% of control thickness. ERG recordings demonstrated significantly improved retinal responses after STING inhibition.
CONCLUSIONS: STING inhibition preserves neuroretina structure and function, highlighting its role in Ndufs4 pathology. This is the first study to show improved ERG responses following treatment in Ndufs4-KO mice, supporting STING as a promising therapeutic target for mitochondrial NADH dehydrogenase deficiency disorders.

Keywords:  NADH dehydrogenase; Ndufs4; STING; complex 1 deficiency; mitochondria; neurodegeneration; retina

DOI:  https://doi.org/10.1016/j.exer.2026.111238
Elife. 2026 Sep 24. pii: RP111419. [Epub ahead of print]15

Developmental synchrony of retinal waves, apoptosis, and angiogenesis in postnatal retina.

Michael A Savage, Cori Bertram, Jean de Montigny, Courtney A Thorne, Rachel Queen, Majlinda Lako, Gerrit Hilgen, Evelyne Sernagor.

  Postnatal mouse retinal development is a multi-faceted process involving the coordinated interaction of spontaneous neural activity as retinal waves, vascular plexus growth, and programmed cell death. While these processes are known to interact at a coarse scale, the specific mechanisms integrating them have remained elusive. Using large-scale, wide-field calcium imaging, high-density multielectrode array recordings, single-cell RNA sequencing, and immunohistochemistry, we characterise a tightly aligned centrifugal expansion pattern during retinal development. This pattern is common to stage II retinal wave onsets, vascular development, Heme oxygenase-1 (Hmox1) expressing microglia, apoptotic cell markers, and a novel set of auto-fluorescent cluster complexes (ACCs) identified in this study. Apoptotic cells are known to upregulate functional pannexin-1 (PANX-1) hemichannels. These voltage-gated channels release purinergic molecules which act as 'eat me' signals to neighbouring microglia. PANX-1 hemichannel blockade with the drug probenecid results in a profound decrease in spontaneous wave frequency and strength, suggesting that retinal waves are indeed triggered by these apoptotic cells. Taken together, our observations suggest that spontaneous waves are initially triggered in hotspots by hyperactive apoptotic retinal ganglion cells (RGCs) in unvascularised retinal areas. These apoptotic cells release purinergic molecules via PANX-1 hemichannels, leading to wave generation. This hyperactivity leads to local hypoxic conditions, which, coupled with high extracellular ATP concentrations, promotes angiogenesis. Once blood vessels reach a particular hotspot, ATP release activates Hmox1-positive microglia, which engulf the dying RGCs, creating the auto-fluorescent clusters. Herein, we present a unified mechanism linking causally linking early neural activity, programmed cell death, and angiogenesis in the mammalian retina.

Keywords:  angiogenesis; apoptosis; calcium imaging; microglia; mouse; neuroscience; retinal development

DOI:  https://doi.org/10.7554/eLife.111419