bims-microg 2026-07-19 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–07–19
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Targeting the microglial phosphatidylethanolamine synthesis pathway promotes GABARAP-associated phagocytosis and Aβ clearance in Alzheimer's disease.
Microglia prune developing cortical blood vessels through PD-1 signaling.
Spatial mapping and senolytic targeting of senescent and disease-associated microglia in aged mouse brain white matter.
Transplantation of human iPSC-derived microglia ameliorates neuropathology and circuit dysfunction in progranulin-deficient mice.
Gut microbiome modulation by Veillonella ratti induces resistance to EAE pathogenesis via microbe-derived metabolites.
Heterogenous microglial reactivity contrasts with stable vascular transcriptional programs in mouse models of Alzheimer's, CADASIL, and Traumatic Brain Injury.
Attenuating AAV-triggered innate immunity in the adult mouse nervous system via cGAS-STING pathway inhibition.
PYGL-driven glycogenolysis impairs microglial autophagic flux via SNAP29 O-GlcNAcylation in Alzheimer's disease.
Targeted Degradation of STING by a Neutrophil Membrane-Coated Nanoplatform Suppresses Microglial Pyroptosis After Subarachnoid Hemorrhage.
CSF1R inhibition exacerbates gamma oscillation disruption and induces network hyperexcitability in APP/PS1 mice.
Aspirin alleviates long-term high-fat diet-induced depressive-like behavior in male mice via suppressing arachidonic acid-mediated microglial activation and neuroinflammation.
RVG-functionalized microglial membrane-coated cerium-gallic acid metal-organic frameworks for multi-target Alzheimer's therapy.
Repurposing trazodone for Alzheimer's disease to modulate soluble ST2 levels and alleviate Alzheimer's pathology.
FPR2 deficiency alleviates LPS-induced depressive-like behaviors in mice by suppressing the microglial CSF1/NLRP3 inflammasome pathway.
Metabolic reprogramming via SIRT2-deficient microglial large extracellular vesicles ameliorates alzheimer's pathology.
A BRD4/p300/SP1 epigenetic cascade drives microglial P2X4R transcription and promotes neuropathic pain.
Peripheral nerve injury-induced upregulation of acyl-CoA synthetase 2 contributes to neuropathic pain via mediating microglial autophagy disruption in the spinal dorsal horn.
EXPRESS: Single-Cell Analysis of Microglia and Monocyte Dynamics Uncovers Distinct TNF-driven Neuroimmune Signatures in Humans after Intracerebral Hemorrhage.
Astrocyte exosomes shield retina from ischemia via CaMKII-autophagy.
High-Throughput CETSA Identifies Small Molecule Modulators of ILT3 (LILRB4) with Functional Activity in Human iPSC-Derived Microglia for Alzheimer's Disease.

Signal Transduct Target Ther. 2026 Jul 15. pii: 284. [Epub ahead of print]11(1):

Targeting the microglial phosphatidylethanolamine synthesis pathway promotes GABARAP-associated phagocytosis and Aβ clearance in Alzheimer's disease.

Seung Jae Hyeon, Seung Chan Kim, Jiyeon Chu, Yeonseo Kim, Chaebin Kim, Uiyeol Park, Zahid Tufail, Phuong Thi Thanh Nguyen, Ahreum Eom, Sojung Kim, Yeyun Kim, Eunkyung Lee, Suhyun Kim, Seung Eun Lee, Jiwan Woo, Jin-A Lee, Kyung Eun Lee, Thor D Stein, Hyunbeom Lee, Junghee Lee, Hoon Ryu.

Alzheimer's disease (AD) is a major cause of dementia and a prevalent age-related neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. Although metabolic activation or dysfunction of microglia is implicated in AD pathogenesis, the phospholipid metabolism-associated signaling mechanisms within microglia remain poorly defined. In this study, we demonstrate that quinolinic acid (QA), a byproduct of tryptophan catabolism via the kynurenine pathway, activates the microglial Kennedy pathway-responsible for de novo phosphatidylethanolamine (PE) biosynthesis-by upregulating the enzymes EPT1 and ETNK1. This activation markedly enhances the synthesis of PE species enriched in polyunsaturated fatty acids. Concurrently, QA significantly increases the expression of gamma-aminobutyric acid receptor-associated protein (GABARAP), promotes its lipidation, and facilitates the GABARAP-associated phagocytosis (GAP) of Aβ oligomers by microglia. Knockdown of EPT1 and ETNK1 attenuated QA-induced PE synthesis and impaired the GAP of Aβ oligomers, whereas inhibition of GABARAP lipidation via STBD1 deconjugase substantially reduced QA-mediated GAP. QA administration upregulated microglial Gabarap expression and decreased the Aβ plaque burden in the hippocampus of AD (5xFAD) mice, whereas Gabarap knockdown abrogated QA-induced microglial clearance of Aβ. Collectively, these findings reveal a paradoxically beneficial role of QA in activating a microglia-specific signaling cascade that promotes PE biosynthesis and GAP, thereby enhancing Aβ clearance and mitigating AD pathology. Targeting the microglial PE synthesis pathway and GAP may represent a promising therapeutic strategy to ameliorate Aβ accumulation and slow AD progression.

DOI: https://doi.org/10.1038/s41392-026-02789-z
Nat Neurosci. 2026 Jul 16.

Microglia prune developing cortical blood vessels through PD-1 signaling.

Mengtian Zhang, Yanyan Wang, Runhua Yang, Fen Ji, Sihan Li, Chenxiao Li, Xinghua Zhao, Hong Li, Jianwei Jiao.

During cerebrovascular development, an initial surplus of vessels is generated and subsequently refined through selective elimination to establish an efficient vascular network. Microglia are pivotal regulators of synaptic refinement and brain circuitry maturation, and despite their close interactions with cerebral vessels, whether and how they contribute to cerebrovascular pruning remains unclear. Here, to address this, we visualized and manipulated microglia-vessel interactions in the frontal cortex of postnatal day 11 mice. We found that microglia progressively approach cerebral vessels and subsequently mediate their pruning. Furthermore, we identify the PD-L1-PD-1 signaling axis as a regulator of microglia-mediated vascular pruning via microglial CD5L secretion. Altogether, our findings uncover a role for microglia in targeting redundant vasculature to facilitate vascular network formation during brain development.

DOI: https://doi.org/10.1038/s41593-026-02378-x
Nat Aging. 2026 Jul;6(7): 1417-1436

Spatial mapping and senolytic targeting of senescent and disease-associated microglia in aged mouse brain white matter.

Chase M Carver, Paul T Gomez, Sonia L Rodriguez, James T Redden, Amanda S Latham, Yooree Ha, Jennifer M Kachergus, Yi Liu, Ji Shi, Tommy Tran, Liguo Wang, Simon Melov, E A Thompson, Marissa J Schafer.

Brain white matter undergoes structural and functional alterations linked to late-life cognitive decline, but the cellular and molecular basis of its selective vulnerability remains incompletely defined. Here, in naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampal-adjacent white matter, particularly in the fimbria. Using regional gene expression profiling, immunolabeling, GeoMx digital spatial profiling and CosMx spatial molecular imaging, we identify an aged brain-exclusive microglial population concentrated in white matter that expresses DAM genes together with a 'SenBrain' senescence gene signature, including galectin-3 (GAL3/Lgals3). Single-cell spatial trajectory analyses suggest that multiple cell fate transitions may give rise to this aged, proinflammatory, senescent- and DAM-linked state. Pharmacogenetic or pharmacological senotherapeutic interventions reduced white matter GAL3+ DAM abundance and restored a more youthful microglial organization in aged fimbria. These findings identify a senescence- and DAM-enriched microglial state as a prominent and partially reversible feature of aged brain white matter.

DOI: https://doi.org/10.1038/s43587-026-01154-7
Mol Neurodegener. 2026 Jul 16.

Transplantation of human iPSC-derived microglia ameliorates neuropathology and circuit dysfunction in progranulin-deficient mice.

Hayk Davtyan, Sarah Naguib, Yuliya Voskobiynyk, Jean Paul Chadarevian, Joia K Capocchi, Jeannie L Giacchino, Ghazaleh Eskandari-Sedighi, Vivianna DeNittis, Jeremy B Ford, Ani Agababian, Jasmine Nguyen, Alina L Chadarevian, Madison S Sutherland, Sepideh Kiani Shabestari, Kayla Tran, Bret Holt, Alissa L Nana, Jiasheng Zhang, Salvatore Spina, Man Ying Wong, Lea T Grinberg, William W Seeley, Eric Huang, Claire D Clelland, Shiaoching Gong, Li Fan, Jeanne T Paz, Mathew Blurton-Jones, Li Gan.

Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglial progenitors into progranulin (Grn)-deficient mice. We find that engraftment of wild-type, but not Grn-deficient, human microglia restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because human microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders.

DOI: https://doi.org/10.1186/s13024-026-00978-6
Exp Mol Med. 2026 Jul 14.

Gut microbiome modulation by Veillonella ratti induces resistance to EAE pathogenesis via microbe-derived metabolites.

Panida Sittipo, Joon-Young Park, Eunike Tiffany, Ara Oh, Subin Moon, Chan Hee Lee, Jae Sang Oh, Tae-Young Kim, Mi-Na Kweon, Jaeseoung Choi, Keon-Hyoung Song, Dong-Woo Lee, Myung Hee Nam, Soo-Jong Hong, Eun-Young Lee, Seong Ran Jeon, Ho-Yeon Song, Bong-Soo Kim, Yun Kyung Lee.

The progression of multiple sclerosis (MS) is potentially influenced by the microbiome. Elucidating host-microbiome interactions in MS may aid in developing microbiome-based applications; however, these interactions remain unclear. Here, we aimed to elucidate how Veillonella ratti MHL0042, isolated from human infant feces, modulates neuroinflammation and disease severity in experimental autoimmune encephalomyelitis, a murine MS model. Whole metagenomic sequencing revealed that V. ratti MHL0042 reshaped disrupted gut microbiota via microbial interactions throughout the intestinal tract. V. ratti MHL0042 administration significantly reduced central nervous system inflammation, notably decreasing CD4+IFN-γ⁺ T cell populations and activated spinal cord microglia. Mechanistically, V. ratti MHL0042 depleted pldA-containing bacteria, involved in phosphatidylethanolamine metabolism, thus elevating dioleoyl phosphatidylethanolamine (DOPE) levels. Increased DOPE was not only detected in the intestinal tract but also extended systemically and reflected in the central nervous system. Exogenous DOPE administration recapitulated the attenuation of experimental autoimmune encephalomyelitis pathogenesis by suppressing microglial activation. These findings highlight the therapeutic applicability of the microbiome and underscore its potential in human disease treatment.

DOI: https://doi.org/10.1038/s12276-026-01779-z
Nat Commun. 2026 Jul 16. pii: 6392. [Epub ahead of print]17(1):

Heterogenous microglial reactivity contrasts with stable vascular transcriptional programs in mouse models of Alzheimer's, CADASIL, and Traumatic Brain Injury.

K D Bjørnholm, H Li, F Del Gaudio, G Mocci, W Shao, E Baldisseri, S B Rao, C Lindblad, A Fletcher-Sandersjöö, E Vázquez-Liébanas, R Pietilä, L Muhl, R Jiang, C Kalantzi, J Cheung, S Jin, M Svensson, S A J Lesnik Oberstein, S Syvänen, M A Mäe, R Torp, U Lendahl, H Karlström, E P Thelin, P Nilsson, M Vanlandewijck.

The extent to which the cerebrovasculature is affected in various brain disorders is still not well understood. To address this, we established a transcriptomic repository of major vascular cell types and microglia to compare the global transcriptomic response in mouse models of three human brain disorders linked to neuroinflammation and associated vascular reactivity: Alzheimer's disease (AD), traumatic brain injury (TBI), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Single-cell analysis of >250,000 cells at different disease stages led to identification of two previously unknown vascular cell subtypes, expanded the endothelial zonation spectrum and allowed for a detailed analysis of the cellular and molecular responses. Surprisingly, most vascular cell types lacked major transcriptomic changes across the three conditions, while microglia exhibited significant, disease-specific transcriptional changes. Notably, microglial responses converged between late-stage TBI and AD, offering insights into the predisposition for neurodegeneration following TBI.

DOI: https://doi.org/10.1038/s41467-026-75367-0
Acta Pharm Sin B. 2026 Jul;16(7): 4389-4409

Attenuating AAV-triggered innate immunity in the adult mouse nervous system via cGAS-STING pathway inhibition.

Yaowei Guo, Jiehao Huang, Yuqi Zhang, Yuxiang Huang, Zeru Li, Yu Xie, Yingqi Cao, Kun Qian, Fan Bai, Wen Li, Wenliang Lei, Gong Chen, Zheng Wu.

  While adeno-associated virus (AAV)-mediated gene delivery has emerged as a promising therapeutic modality for neurological disorders, dose-dependent immune responses remain a critical barrier to clinical translation. Here we reveal the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway as a key mediator of innate immune activation following intracranial AAV administration. Through comparative analyses in genetic and pharmacological intervention models, we demonstrate that STING signaling mediates key neuroinflammatory sequelae including glia reactivation, cytotoxic T cell infiltration, and neuronal injury. Mechanistically, microglia serve as the predominant sentinels detecting AAV immunogenicity via cGAS-STING activation. Therapeutic inhibition of this pathway by either microglia depletion or antagonism of STING by small molecules significantly mitigates high-dose AAV9-induced neurotoxicity while enhancing transgene delivery efficacy. Our work delineates a unified mechanistic framework linking AAV-triggered DNA sensing to neuroinflammatory pathology, and provides two clinically actionable approaches to decouple therapeutic gene delivery from detrimental immune activation in nervous system targeted gene therapy.

Keywords:  AAV; Gene therapy; Innate immunity; Microglia; Nervous system; Neuroinflammation; cGAS–STING

DOI:  https://doi.org/10.1016/j.apsb.2026.04.001
Acta Pharm Sin B. 2026 Jul;16(7): 4367-4388

PYGL-driven glycogenolysis impairs microglial autophagic flux via SNAP29 O-GlcNAcylation in Alzheimer's disease.

Yi Ding, Shi-Yao Li, Wen-Feng Zhang, Mao-Mao Chu, Xue-Jie Wang, Yu-Ge Zhang, Hui-Wen Zhang, Yu-Tong Zhang, Lu Xu, Xue Liu, Tsuyoshi Morita, Otto Baba, Zi-Jian Ren, Yong-Jie Zhang, Zhi-Yuan Zhang, Lei Li.

  Aberrant metabolic alterations underlie microglial dysfunction, which plays an important role during neurodegenerative progression. However, the role of aberrant glycogen metabolism remains elusive. Here, we identified glycogen accumulation and upregulated glycogenolytic enzymes in brain microglia from patients with Alzheimer's disease (AD) and transgenic animal models. Particularly, the principal microglial glycogenolytic enzyme PYGL exhibited the most notable spatiotemporal upregulation during disease progression. Specific knockdown of microglial PYGL ameliorated neuropathological changes and cognitive deficits in AD mice. Bioinformatics analysis and experimental validation confirmed that enhancing microglial autophagic flux-dependent Aβ clearance was the underlying mechanism. Furthermore, among all possible glycogenolytic pathways, PYGL downregulation primarily reduced hexosamine biosynthesis pathway activity, diminished UDP-GlcNAc and O-GlcNAcylation of the autophagy key protein SNAP29, and thereby facilitated formation of the SNARE complex, which is essential for autophagosome-lysosome fusion. These findings reveal a glycogenolysis-driven post-translational pathway regulating microglial autophagy, establishing PYGL as a therapeutic target for AD.

Keywords:  Autophagosome–lysosome fusion; Autophagy; Glycogen metabolism; Glycogenolysis; O-GlcNAcylation; PYGL; SNAP29; SNARE complex

DOI:  https://doi.org/10.1016/j.apsb.2026.04.017
Adv Sci (Weinh). 2026 Jul 11. e76553

Targeted Degradation of STING by a Neutrophil Membrane-Coated Nanoplatform Suppresses Microglial Pyroptosis After Subarachnoid Hemorrhage.

Ruotian Zhang, Kaikun Yuan, Haoyu Zou, Hanfeng Qin, Jiale Liu, Jianda Sun, Feifan Zhang, Yuankui Wang, Tong Wang, Jiaxing Dai, Chunxu Li, Yichi Chen, Yingfeng Tu, Huaizhang Shi.

  Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease in which neuroinflammation and neuronal death critically contribute to poor outcomes. Here, we identify aberrant STING activation as a key driver of microglial pyroptosis and post-SAH injury. Transcriptomic and biochemical analyses support a close association between STING signaling and microglial pyroptosis, with MAPK signaling acting as a functionally relevant downstream pathway. Based on this mechanistic insight, we engineered MG1 peptide-functionalized, neutrophil membrane-coated STING-PROTAC nanoparticles (MG1@NM-Px) to enable blood-brain barrier penetration, microglia-targeted delivery, and efficient STING degradation in vivo. This catalytic degradation suppressed the inflammasome-related activation and GSDME-associated pyroptotic signaling, reduced pro-inflammatory cytokine secretion, and prevented neuronal apoptosis. Histopathological examination showed preserved Nissl body integrity, while behavioral testing revealed significant improvements in neurological function. Collectively, this engineered neutrophil membrane-coated STING-PROTAC nanoplatform effectively degrades STING, inhibits microglial pyroptosis, and provides robust neuroprotection in SAH. This work establishes a novel biomimetic nanomedicine strategy for SAH therapy and opens new avenues for treating neuroinflammation-related disorders.

Keywords:  PROTAC; STING; biomimetic nanoparticles; microglial pyroptosis; subarachnoid hemorrhage

DOI:  https://doi.org/10.1002/advs.76553
Brain. 2026 Jul 14. pii: awag147. [Epub ahead of print]

CSF1R inhibition exacerbates gamma oscillation disruption and induces network hyperexcitability in APP/PS1 mice.

Hugh J Delaney, Sadia Islam, Dáire Healy, Ross Oglesby, Meghamsh Konda, Gudo M Rietman, Rebecca Lynch, Arshed Nazmi, James T Murray, Mark O Cunningham, Colm Cunningham.

  Alzheimer's Disease is the most common neurodegenerative disease worldwide, but significant gaps in pathophysiological understanding have hampered development of disease-modifying therapies. In Alzheimer's disease, neurophysiological function is impaired, with gamma frequency oscillations - thought to be essential for higher-order cognitive processes - disrupted in both patients and animal models. However, the mechanisms driving these disruptions are unclear and, in particular, the role of neuroinflammation in these changes is poorly understood. In this study, we investigated neuronal network dynamics in acute brain slices from APP/PS1 transgenic mice. Gamma frequency oscillations had significantly reduced amplitude in APP/PS1 brain slices at 9-11 months, accompanied by an increase in beta frequency power and heightened epileptiform activity. This is suggestive of a slowing in neuronal oscillations, considered a neurophysiological hallmark of Alzheimer's disease. Immunohistochemical analysis revealed a reduction in parvalbumin- and somatostatin-positive inhibitory interneuron populations. Treatment with gabazine demonstrated increased network sensitivity to GABAA receptor antagonism, further indicating compromised inhibitory control in APP/PS1. As these altered oscillatory dynamics correlated with microglial reactivity, we hypothesised a causal role for microglia. Administration of the CSF1R inhibitor GW2580 reduced microglial proliferation, attenuated development of the disease-associated microglial phenotype and partially rescued synaptic loss; but, had no significant impact on amyloid plaque burden or cognitive deficits. Unexpectedly, GW2580 treatment exacerbated neuronal network hyperactivity and the incidence and complexity of epileptiform activity. Microglia in GW2580-treated mice showed reduced CD68 expression and decreased engulfment of synaptic elements, potentially facilitating the persistence of hyperexcitable synapses. These findings support a role of microglia in regulating neuronal network homeostasis and caution against indiscriminate suppression of microglial activity in Alzheimer's disease. Therapeutic strategies targeting microglia must account for their homeostatic functions to avoid adverse effects on neuronal network stability.

Keywords:  Alzheimer’s disease; CSF1R inhibition; gamma oscillations; microglia; neuronal network hyperexcitability; synaptic pruning

DOI:  https://doi.org/10.1093/brain/awag147
Mol Psychiatry. 2026 Jul 15.

Aspirin alleviates long-term high-fat diet-induced depressive-like behavior in male mice via suppressing arachidonic acid-mediated microglial activation and neuroinflammation.

Binbin Zhao, Yajuan Fan, Qingyan Ma, Jinyu Zhang, Xiaoying Jin, Yuan Peng, Wenyu Xi, Jiawen Wang, Jing Yang, Shan Wang, Mengfan Zhang, Hua Shao, Min Jia, Binglong Wen, Bin Yan, Yijie Guo, Wei Wang, Feng Zhu, Yunpeng Wang, Yanan Wang, Xiancang Ma.

While Western dietary patterns are increasingly linked to neuropsychiatric disorders, the causal mechanisms by which chronic high-fat diet (HFD) contributes to depression remain elusive. Here, we demonstrate that prolonged ( ≥ 10 weeks) HFD exposure in mice robustly induces depressive-like behaviors, phenocopying chronic stress models. Integrating multi-omics and targeted lipidomics, we reveal that HFD-induced behavioral deficits are underpinned by gut microbiota dysbiosis and a profound disruption of polyunsaturated fatty acid (PUFA) homeostasis. This disruption is characterized by a surge in pro-inflammatory ω-6 metabolites, particularly arachidonic acid (AA), alongside a concomitant reduction in anti-inflammatory ω-3 metabolites. These lipid perturbations strongly correlate with marked microglial activation and elevated pro-inflammatory cytokine levels (IL-6, TNF-α, CCL2) in the prefrontal cortex and hippocampus. Functionally, AA supplementation alone was sufficient to recapitulate depressive-like behaviors in vivo and, through neuron-microglia co-culture assays, directly induce pro-inflammatory microglial activation, NF-κB pathway upregulation, and subsequent synaptic impairment in vitro. Critically, therapeutic intervention with aspirin, a dual COX-1/COX-2 inhibitor, effectively reversed HFD-induced behavioral deficits. This protection was mediated by a dual mechanism: directly inhibiting microglial hyperactivation and normalizing the neuroinflammatory milieu by suppressing the biosynthesis of pro-inflammatory ω-6-derived prostanoids, including AA and 12-HETE. Collectively, our findings identify AA as a critical etiological link between HFD and neuroinflammation, establishing a mechanistic framework for "metabolic depression." The profound therapeutic efficacy of aspirin validates the AA metabolic pathway, specifically COX-1/COX-2, as a promising and targetable node for intervention, offering translational insights for the burgeoning field of nutritional psychiatry.

DOI: https://doi.org/10.1038/s41380-026-03752-8
J Colloid Interface Sci. 2026 Jul 13. pii: S0021-9797(26)01310-X. [Epub ahead of print]724(Pt 2): 141133

RVG-functionalized microglial membrane-coated cerium-gallic acid metal-organic frameworks for multi-target Alzheimer's therapy.

Fengmei Yang, Yutong Chen, Yujiao Yan, Ruixin Zhao, Liran Deng, Die Tian, Qi Wang, Meng Xie.

  Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by aberrant β-amyloid (Aβ) aggregation, oxidative stress, neuroinflammation, and disrupted metal ion homeostasis, which limit the efficacy of conventional single-target therapies. To address these intertwined pathological processes, we developed a multifunctional nanotherapeutic platform based on a cerium-gallic acid bio-metal-organic framework (CeGA-MOF). Reversible Ce3+/Ce4+ redox cycling enables efficient reactive oxygen species (ROS) scavenging, while gallic acid serves as both an organic ligand and metal chelator, inhibiting metal ion-mediated Aβ aggregation and alleviating oxidative stress-associated neurotoxicity, along with its intrinsic anti-inflammatory activity. To enhance in vivo stability and brain delivery, CeGA-MOF was coated with microglial membranes and functionalized with rabies virus glycoprotein (RVG) peptide, yielding a biomimetic nanosystem, CeGA-MOF/B/R. The microglial membrane provides immune evasion and inflammation-guided targeting, while RVG facilitates blood-brain barrier penetration. In vitro, CeGA-MOF/B/R effectively chelates Cu2+, Zn2+, and Fe3+, suppresses metal ion-induced Aβ aggregation, and protects neurons. In APP/PS1 transgenic mice, it reduced cerebral Aβ, promoted anti-inflammatory microglial polarization, and improved learning and memory, highlighting its potential as a biomimetic nanoplatform for synergistic AD therapy.

Keywords:  Alzheimer's disease; Anti-inflammatory; Antioxidant; Aβ; MOFs

DOI:  https://doi.org/10.1016/j.jcis.2026.141133
Proc Natl Acad Sci U S A. 2026 Jul 21. 123(29): e2536489123

Repurposing trazodone for Alzheimer's disease to modulate soluble ST2 levels and alleviate Alzheimer's pathology.

Daniel Y K Wong, Wing-Yu Fu, Hyebin Uhm, Yuanbing Jiang, Yuki C C Yip, Vincent C T Mok, Timothy C Y Kwok, Li Ouyang, Amy K Y Fu, Nancy Y Ip.

  Alzheimer's disease (AD) is a multifactorial disorder involving various pathological mechanisms, such as amyloidosis, immune dysfunctions, and synaptic impairments, which are important therapeutic targets. Repurposing drugs to target these mechanisms offers a promising approach to reduce the costs and duration of drug development. Genetic studies underscore the critical role of microglial clearance of amyloid-beta (Aβ) in AD pathogenesis. Specifically, soluble ST2 (sST2)-one of the two major isoforms of the ST2 protein encoded by the IL1RL1 (interleukin-1 receptor-like 1) gene-acts as a decoy receptor isoform that interferes with IL-33/ST2 signaling and has been identified as a disease-modifying factor that impairs microglial Aβ clearance functions. In this study, we investigated drug repurposing opportunities to modulate sST2 levels and alleviate AD pathologies. Unbiased screening of commonly used medications in AD patients, followed by validation in model systems, identified trazodone-an antidepressant used to treat major depressive disorder-as a leading negative regulator of sST2. Trazodone primarily suppresses sST2 expression through its antagonistic effects on adrenergic signaling. In the APP/PS1 transgenic mouse model of AD, trazodone treatment enhanced microglial interaction with Aβ and alleviated Aβ pathology. Furthermore, trazodone reduced neurodegeneration and rescued synaptic deficits in APP/PS1 mice. Comprehensive molecular profiling of APP/PS1 mouse brains showed that trazodone restored the expression of synaptic proteins critical for synaptic integrity and plasticity. Overall, these findings demonstrate that trazodone is a promising repurposing candidate for AD that targets underlying immune dysfunctions and synaptic impairment.

Keywords:  disease-modifying factor; drug screening; interleukin-33; microglia; synaptic function

DOI:  https://doi.org/10.1073/pnas.2536489123
J Neuroinflammation. 2026 Jul 16.

FPR2 deficiency alleviates LPS-induced depressive-like behaviors in mice by suppressing the microglial CSF1/NLRP3 inflammasome pathway.

Hanqi Wang, Yijun Chen, Junna Chang, Zhen Liu, Yang Yu.

  Depression is one of the most prevalent psychiatric disorders worldwide, yet its pathogenesis remains unclear. Here, we aimed to investigate the effects of formyl peptide receptor 2 (FPR2), a key regulator of innate immunity and inflammation, on lipopolysaccharide (LPS)-induced depression-related behaviors in mice after intraperitoneal administration, and to elucidate its regulatory mechanisms in microglia. FPR2 knockout (Fpr2-/-) significantly attenuated LPS-induced depressive and anxiety-like behaviors in mice. LPS markedly increased FPR2 expression in microglia of the prefrontal cortex (PFC) and hippocampus, while only a minimal increase was observed in neurons. FPR2 deficiency alleviated LPS-induced microglial activation and reduced neuronal synaptic alterations. RNA sequencing and validation experiments confirmed that FPR2 deletion substantially decreased LPS-induced microglial NLRP3 inflammasome activation and IL-1β levels in the brain. Mechanistically, FPR2 regulated downstream NLRP3 activation by modulating CSF1, and FPR2/CSF1 activation was governed by its upstream ligand, serum amyloid A (SAA). Analysis of public clinical datasets revealed that SAA1 levels were significantly upregulated in the orbital ventral PFC of patients with major depressive disorder (MDD) and in the plasma of patients with late-life depression. These findings demonstrate that the SAA/FPR2/CSF1/NLRP3 pathway mediates LPS-induced depressive-like behaviors by regulating microglial activation and neuroinflammation.

Keywords:  Anxiety; Colony-stimulating factor 1 (CSF1); Depression; Formyl peptide receptor 2 (FPR2); Lipopolysaccharide (LPS); Microglia; NOD-like receptor protein 3 (NLRP3); Neuroinflammation; RNA sequencing; Serum amyloid A (SAA)

DOI:  https://doi.org/10.1186/s12974-026-03963-4
J Neuroinflammation. 2026 Jul 17.

Metabolic reprogramming via SIRT2-deficient microglial large extracellular vesicles ameliorates alzheimer's pathology.

Xiaolu Tang, Rui Chen, Jiawei Xing, Qing Huang, Lv Luo, Chaoyue Ouyang, Fubin Ma, Jie Wen, Jiahao Zhang, Lingyun Kong, Yujie Cai, Yan Wang, Lili Cui.

   BACKGROUND: Current therapies for Alzheimer's disease (AD) offer only symptomatic relief, highlighting the urgent need for disease-modifying approaches capable of halting or reversing neurodegeneration. Extracellular vesicles (EVs) have attracted growing interest as therapeutic vehicles owing to their inherent capacity to bypass the blood-brain barrier and deliver complex biological cargo to the central nervous system.
METHODS: Here, we examined whether large EVs (LEVs) derived from microglia with stable Sirtuin-2 knockdown (SIRT2-KD) confer the neuroprotective effects associated with SIRT2 inhibition. LEVs harvested from SIRT2-KD microglia were administered intranasally to APP/PS1 mice. We assessed microglial uptake of LEVs, along with subsequent changes in cellular metabolism, migration toward amyloid-beta (Aβ) plaques, phagocytic activity, and downstream pathological and behavioral outcomes. Proteomic and acetylomic profiling were employed to characterize the molecular cargo of LEVs-SIRT2-KD.
RESULTS: LEVs-SIRT2-KD were readily internalized by microglia in vivo following intranasal delivery. Uptake of these vesicles markedly enhanced microglial bioenergetics, driving coordinated upregulation of both oxidative phosphorylation and glycolysis. This metabolic shift was accompanied by improved microglial recruitment to Aβ plaques and increased phagocytic clearance. Consequently, treated mice showed reduced Aβ plaque deposition, restored synaptic integrity, and reversal of cognitive deficits. Proteomic and acetylomic analyses revealed that LEVs-SIRT2-KD are selectively enriched in proteins and acetylation modifications linked to energy metabolism and phagocytic function, offering a mechanistic basis for the observed metabolic reprogramming.
CONCLUSION: Together, these results identify LEVs as a critical vesicle subtype mediating the effects of SIRT2 knockdown and support a cell-free therapeutic strategy for AD centered on EVs-driven metabolic reprogramming of microglia.

Keywords:  Alzheimer’s disease (AD); Extracellular vesicles (EVs); Glycolysis; Oxidative phosphorylation; SIRT2

DOI:  https://doi.org/10.1186/s12974-026-03956-3
J Neuroinflammation. 2026 Jul 17.

A BRD4/p300/SP1 epigenetic cascade drives microglial P2X4R transcription and promotes neuropathic pain.

Daojuan Wang, Tingyu Wang, Yin Li, Xinye Yu, Shenquan Cai, Chun Wang, Yihan Wang, Zhengquan Zhu, Ying Huang, Yong Wang, Wangsen Cao, Gaojian Tao.

  Persistent upregulation of the purinergic receptor P2X4R is strongly associated with microglial activation in neuropathic pain, yet the epigenetic mechanisms linking chromatin remodeling to its dysregulation remain unclear. Here, we delineate a hierarchical epigenetic cascade that promotes transcriptional activation of P2X4R in spinal microglia following nerve injury. In a mouse spared nerve injury (SNI) model, microglial activation was accompanied by increased expression of P2X4R and the histone acetyltransferase p300, together with enhanced histone acetylation (H3K9ac, H3K27ac, H4K5ac, and H4K8ac) and increased chromatin accessibility at the P2rx4 promoter. Microglia-specific deletion of p300 blunted injury-induced histone acetylation and suppressed P2X4R upregulation. We further demonstrate that the acetylation reader BRD4 is recruited to these regions and cooperates with the transcription factor SP1 to drive P2rx4 transcription, supported by chromatin analyses revealing inducible assembly of a BRD4-p300-SP1 axis. Disruption of this cascade via p300 inhibition (C646) or BRD4 blockade (JQ1) attenuated spinal neuroinflammation and alleviated nociceptive hypersensitivity. Notably, reactivation of P2X4R by BzATP largely reversed the analgesic effects of BRD4 inhibition, establishing P2X4R as a critical downstream effector. Collectively, these findings support a p300-BRD4-SP1 epigenetic cascade linking chromatin remodeling to microglia-mediated neuropathic pain, highlighting this pathway as a potential therapeutic target.

Keywords:  BRD4; Histone acetylation; Microglia activation; Neuropathic pain; P2X4R; P300

DOI:  https://doi.org/10.1186/s12974-026-03965-2
Brain Behav Immun. 2026 Jul 12. pii: S0889-1591(26)00662-8. [Epub ahead of print]138 106914

Peripheral nerve injury-induced upregulation of acyl-CoA synthetase 2 contributes to neuropathic pain via mediating microglial autophagy disruption in the spinal dorsal horn.

Yiming Qiao, Liren Li, Liying Bai, Yan Gao, Xueli Wang, Lili Yv, Haozhuang Yuan, Sailong Wei, Ji-Tian Xu.

  Acyl-CoA synthetase 2 (ACSS2), by producing acetyl-coenzyme A from acetate in the nucleus, facilitates histone acetylation and regulates gene expression. However, the role of ACSS2 in neuropathic pain remains unclear. Herein, we found that lumbar 5 spinal nerve ligation (SNL) increased ACSS2 expression predominately in microglia of the spinal dorsal horn. This increase was accompanied by elevated histone H3K27 acetylation (H3K27ac), enhanced raptor expression, activated mTORC1/TFEB signaling, raised p62, and reduced LC3II/LC3I ratio. Repeated intrathecal or intravenous injections of ACSS2 inhibitor (ACSS2i) partially prevented development of, and reversed established, neuropathic pain in male and female rats. Microglia-specific AAV-F4/80-ACSS2 shRNA injection into L5 spinal dorsal horn alleviated SNL-induced pain hypersensitivity, counteracted the increase in H3K27ac and rescued mTORC1/TFEB signaling-mediated autophagy impairment. SNL-enhanced binding of SP1, a transcriptional regulator of raptor, and the elevation of H3K27ac at the raptor promoter were inhibited by AAV-F4/80-ACSS2 shRNA. The increases of IL-1β and TNF-α production after SNL were also reversed by these interventions. Microglia-specific Acss2 knockout (Acss2cKO) mitigated SNL-induced abnormal pain, and prevented microglial autophagy disruption in male and female mice. ACSS2i treatment decreased H3K27ac, reduced SP1 binding with raptor promoter, and restored autophagy disruption in cultured BV2 cells following LPS stimulation. In addition, knockdown of ACSS2 specifically in neurons or astrocytes partially reduced pain following SNL. Collectively, our findings suggest that the peripheral nerve injury-induced upregulation of ACSS2 in the spinal dorsal horn contributes to neuropathic pain might partially through regulating raptor expression and subsequently activating mTORC1/TFEB signaling-mediated microglial autophagy disruption.

Keywords:  Acyl-CoA synthetase 2; Autophagy; Histone acetylation; Microglia; Neuroinflammation; Neuropathic pain; Spinal cord

DOI:  https://doi.org/10.1016/j.bbi.2026.106914
J Cereb Blood Flow Metab. 2026 Jul 15. 271678X261471282

EXPRESS: Single-Cell Analysis of Microglia and Monocyte Dynamics Uncovers Distinct TNF-driven Neuroimmune Signatures in Humans after Intracerebral Hemorrhage.

Yuki Kawamura, Conor W Johnson, Jonathan DeLong, Lucas Paulo de Lima Camillo, Sofia E Velazquez, Munetomo Takahashi, Hannah E Beatty, Ryan Hebert, Branden J Cord, Charles Matouk, Mike Askenase, Lauren H Sansing.

Innate immune cells contribute to both secondary brain injury and repair following intracerebral hemorrhage (ICH). However, the signaling pathways governing initial inflammatory and subsequent reparative myeloid programs in living patients remain poorly understood. To better characterize mononuclear phagocyte cell changes over time, we generated a single-cell transcriptomic dataset of paired hematoma clot evacuates and peripheral blood samples from 10 patients following ICH (5 - 290 hours). We identified distinct populations of activated and TNF-low microglia, as well as a highly activated population of CD14+ monocytes in the hematoma. Perturbation analysis identified TNF signaling as the primary driver of hematoma monocyte activation. Custom temporal trajectory analysis using single-cell foundation model embeddings found that this TNF response in monocytes was transient, peaking early after hemorrhage and decreasing over the following 48 hours as monocytes shifted to reparative transcriptional programs. Transiently activated microglia emerged as the likely acute source of TNF among analyzed populations, signaling through monocyte TNFR2. Surprisingly, acute TNF signaling in CD14+ monocytes was also associated with better severity-adjusted neurological outcomes both in our cohort and an independent validation cohort. These findings suggest acute TNF signaling between activated microglia and hematoma-associated monocytes, particularly through TNFR2, may contribute to recovery following ICH.

DOI: https://doi.org/10.1177/0271678X261471282
Ann Med. 2026 Dec;58(1): 2702698

Astrocyte exosomes shield retina from ischemia via CaMKII-autophagy.

Dan He, Hua Li, Chunling Wei, Chen Chen, Juanjuan Li.

   BACKGROUND: Retinal ischemia-reperfusion (RIR) injury impairs vision through microvascular damage and inflammation. While astrocyte-derived exosomes (ADEs) offer neuroprotection, their role in protecting retinal microvasculature is unclear. This study investigates ADEs' effects on retinal microvascular endothelial cells (RMECs) in RIR.
METHODS: ADEs were isolated from astrocytes. Mouse RIR and cellular oxygen-glucose deprivation/reoxygenation (OGD/R) models were used. We assessed ADEs' impact on retinal microcirculation, microglial activation, and RMEC function. The roles of neurogranin and the CaMKII-autophagy pathway were examined using inhibitors.
RESULTS: ADEs, rich in neurogranin, alleviated RIR-induced microvascular damage and suppressed OGD/R-triggered pro-inflammatory microglial activation. This was associated with increased neurogranin, CaMKII phosphorylation, and autophagy in microglia. Consequently, ADEs counteracted the harmful effects of activated microglia on RMEC proliferation, migration, and tube formation. Inhibiting CaMKII or autophagy blocked ADEs' protective benefits without altering neurogranin, placing the CaMKII-autophagy axis downstream.
CONCLUSION: ADEs protect RMECs from RIR injury by modulating microglial responses via a neurogranin-CaMKII-autophagy mechanism, revealing their therapeutic potential for retinal microvascular protection.

Keywords:  Astrocyte-derived exosomes (ADEs); CaMKII-autophagy axis; microglia; neurogranin; retinal ischemia-reperfusion (RIR); retinal microvascular endothelial cells

DOI:  https://doi.org/10.1080/07853890.2026.2702698
ACS Med Chem Lett. 2026 Jul 09. 17(7): 1647-1654

High-Throughput CETSA Identifies Small Molecule Modulators of ILT3 (LILRB4) with Functional Activity in Human iPSC-Derived Microglia for Alzheimer's Disease.

Somaya A Abdel-Rahman, Moustafa Gabr.

  Immune inhibitory signaling in microglia contributes to impaired amyloid-β (Aβ) clearance and neuroinflammation in Alzheimer's disease (AD), yet small molecule modulators targeting these pathways remain largely unexplored. Here, we report the development of a high-throughput cellular thermal shift assay (HT-CETSA) platform for identification of small molecule binders targeting the inhibitory immune receptor ILT3 (LILRB4). Screening of ∼40 000 compounds yielded multiple validated hits, including IB15C, a submicromolar ILT3 binder identified through preliminary structure-activity relationship optimization. Orthogonal validation by microscale thermophoresis, surface plasmon resonance, docking, and site-directed mutagenesis confirmed direct and target-specific ILT3 engagement. Functionally, IB15C disrupted the ILT3-ApoE interaction and restored microglial activity in human iPSC-derived microglia, reducing SHP1/2 and NF-κB signaling, suppressing IL-1β secretion, and enhancing Aβ uptake. IB15C also demonstrated favorable in vitro pharmacokinetic and safety properties, supporting further development of ILT3-targeted neuroimmune therapeutics.

Keywords:  Alzheimer’s disease; CETSA; ILT3; LILRB4; Microglia

DOI:  https://doi.org/10.1021/acsmedchemlett.6c00244