bims-microg 2026-09-20 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–09–20
eighteen papers selected by
Marcus Karlstetter, Universität zu Köln

Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
CD36-mediated lipid-accumulation in reactive microglia contributes to retinal degeneration via the NLRP3-IL-1β pathway in mice.
Microglia deploy TAM receptors to kill motor neurons in a mouse model of amyotrophic lateral sclerosis.
Microglial TSPAN4-Dependent Migrasomes Promote Pathological Retinal Neovascularization via Immune-Vascular Crosstalk.
Targeting glial PD-1/PD-L1 restores microglial homeostasis and reduces neuronal hyperactivity in an Alzheimer's disease model.
Cellular transcriptomic signatures underpinning the heterogeneity of depression in Alzheimer's disease.
CX3CL1/CX3CR1-dependent microglial phagocytosis of oligodendrocyte precursor cells contributes to sevoflurane-induced myelination impairments in neonatal mice.
DREADDs-Gi mediated inhibition of myeloid cells leads to anti-inflammatory signalling, shrinkage of microglia and acute heart failure in Cx3cr1Cre mice.
NEMO (IKKγ) citrullination in microglia promotes neuroinflammation in the post-ischemic brain.
Microglial dectin-1/Clec7a in an alzheimer's disease model: a double-edged sword across the lifespan.
Transcriptomic landscape of microglia in mouse models of social dysfunction and oxytocin-mediated recovery.
Let-7a-5p/SHIP-1 Axis Drives SARS-CoV-2 Spike-1-Induced Microglial Pyroptosis.
AI-guided discovery of a brain-penetrant LILRB4 inhibitor active in microglial and 5xFAD models of Alzheimer's disease.
Microglia Ablation and Downstream Effects in the Cerebrospinal Fluid Proteome.
Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement.
ELAVL3 Exacerbates Brain Injury and Cognitive Dysfunction in Mice After Cardiac Arrest by Increasing S100B mRNA Stability to Promote Microglia Activation.
Multiomic Integration Reveals Novel miRNA-mRNA-Protein Expression Profile in the Aged Female Retina.
Transcriptional changes in microglial Kcnk2 during fear memory reconsolidation and TREK-1-associated regulation of TNF-α invitro.

Nat Commun. 2026 Aug 15. pii: 9829. [Epub ahead of print]17(1):

Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.

Hyunmin Cho, Ruhi Sayana, Abhishek Koladiya, Pasqualina Colella, Sangkyun Cho, James W S Jahng, Juan Jose Vasquez, Jessica Arozqueta Basurto, Joseph C Wu, Natalia Gomez-Ospina.

Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency that leads to progressive neurodegeneration and cardiomyopathy. Effective disease-modifying therapies remain limited. Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.

DOI: https://doi.org/10.1038/s41467-026-76775-y
Nat Commun. 2026 Aug 15. pii: 9803. [Epub ahead of print]17(1):

CD36-mediated lipid-accumulation in reactive microglia contributes to retinal degeneration via the NLRP3-IL-1β pathway in mice.

Tian Zhou, Ziqi Yang, Hong Zhou, Biyan Ni, Yang Zhou, Jingpeng Li, Minglu Ma, Huaicheng Wang, Peng An, Huiyi Xu, Xiaojing Lin, Shiya Lin, Shasha Wang, Shida Chen, Lixia Lin, Xialin Liu, Chang He.

Microglia are central regulators of retinal immune homeostasis, yet their pathogenic states in retinal degeneration remain less well understood. Here we identified a distinct subset of lipid-accumulated reactive microglia (aLARM), using scRNA sequencing and spatial transcriptomics in NaIO3-induced retinal degeneration mice, predominantly localized to the outer retina. aLARM were conserved across mouse models and patients and uniquely marked by high CD36 expression. Microglia-specific CD36 deletion abolished aLARM-mediated inflammation and degeneration, whereas subretinal transplantation of CD36+ aLARM exacerbated retinal structural destruction and functional impairment. Mechanistically, CD36+ aLARM activated NLRP3 inflammasome and produced IL-1β, engaging IL-1R1 on microglia/macrophages and pericytes/SMCs to amplify a feed-forward inflammatory circuit. Therapeutic CD36 blockade with the neutralizing antibody FA6-152 reduced aLARM formation and protected against neurodegeneration. Together, our findings highlight CD36+ aLARM as a targetable pathogenic microglial population linking neuroinflammation to retinal degeneration, providing a potential foundation for microglia-based precision therapies.

DOI: https://doi.org/10.1038/s41467-026-76685-z
Nat Commun. 2026 08 15. pii: 9837. [Epub ahead of print]17(1):

Microglia deploy TAM receptors to kill motor neurons in a mouse model of amyotrophic lateral sclerosis.

Youtong Huang, Ananya Mavinkurve, Bristy Sabikunnahar, Beth Stevens, Greg Lemke.

Activation of microglia is a prominent feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that leads to the death of motor neurons. A key component of this activation is elevated expression of the TAM receptor tyrosine kinases Axl and Mer (gene name Mertk). Here we show that germline and microglial-restricted inactivation of the Axl and Mertk genes in the SOD1G93A mouse model of ALS leads to an extension of lifespan, which is tied to the preservation of cholinergic motor neurons and neuromuscular synapses. Also elevated on SOD1G93A neuronal surfaces is the essential TAM co-ligand phosphatidylserine, a potent 'eat-me' signal through which apoptotic cells are engulfed by microglia. Correspondingly, we find that microglial lysosomes are filled with the remains of cholinergic neurons in the SOD1G93A spinal cord, whereas this accumulation is markedly reduced in the SOD1G93AAxl-/-Mertk-/- cord. Together, these results suggest that microglia phagocytically kill living neurons, and thereby hasten death in ALS.

DOI: https://doi.org/10.1038/s41467-026-76728-5
Adv Sci (Weinh). 2026 Sep 13. e77711

Microglial TSPAN4-Dependent Migrasomes Promote Pathological Retinal Neovascularization via Immune-Vascular Crosstalk.

Jingyi Xu, Jingfan Wang, Pengfei Ge, Qinyuan Gu, Hongying Li, Yuanyuan Fan, Haiyue Xie, Yangyang Lu, Yifan Lin, Xinjing Wu, Chengkun Wang, Ping Xie, Zizhong Hu.

  Diabetic retinopathy (DR) is a leading cause of vision loss among working-age adults worldwide, yet the microglial mechanisms driving pathological retinal neovascularization (RNV) remain incompletely understood. By integrating single-cell transcriptomic profiling of human fibrovascular membranes with murine disease models, we identified a TSPAN4-associated microglial state characterized by a pro-angiogenic and activated transcriptional program. Spatially, TSPAN4-expressing microglia accumulated around pathological vascular tufts, and suppression of TSPAN4 attenuated RNV in the oxygen-induced retinopathy (OIR) model. Under high-glucose and hypoxic conditions, microglia upregulated TSPAN4 expression and triggered the biogenesis of migrasomes along retraction fibers. Microglia-derived migrasomes were sufficient to promote endothelial angiogenic responses in vitro and pathological neovascularization in vivo. Mechanistically, transcriptomic analyses revealed that microglial migrasomes exerted pro-angiogenic effects by activating the HIF-1α/VEGF pathway in endothelial cells. In parallel, migrasomes reinforced a pro-inflammatory microglial phenotype, establishing a pathogenic feed-forward loop that amplified retinal vascular injury. Collectively, our findings define TSPAN4-dependent migrasome formation as a critical mechanism through which microglia promote pathological RNV and uncover migrasome-mediated communication as a previously unrecognized mode of immune-vascular crosstalk. Targeting the microglial TSPAN4-migrasome axis represents a promising therapeutic strategy for neovascular retinal diseases.

Keywords:  TSPAN4; diabetic retinopathy; microglia; migrasomes; retinal neovascularization

DOI:  https://doi.org/10.1002/advs.77711
Sci Adv. 2026 Sep 18. 12(38): eadx0731

Targeting glial PD-1/PD-L1 restores microglial homeostasis and reduces neuronal hyperactivity in an Alzheimer's disease model.

Taeyoung Park, Leechung Chang, Seung Won Chung, Seowoo Lee, Sungjun Bae, Carlo Condello, Yong Ho Kim, Jaecheol Lee, Han-Joo Kim, Ho-Keun Kwon, Minah Suh.

Alzheimer's disease (AD) involves complex neuroimmune dysregulation, and the role of immune checkpoint pathways in regulating neuro-glial interactions and intrinsic glial homeostasis remains unclear. In AD, glial expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) is elevated in mouse models and human patients, suggesting involvement of immune checkpoint signaling in glial function. To define the role of this pathway in the AD brain, we locally modulated PD-1/PD-L1 signaling by intracortical anti-PD-L1 injection in 8-10-month-old 5xFAD mice, combined with in vivo two-photon imaging and quantitative functional analyses. Brain-intrinsic PD-L1 blockade reshaped the local glial microenvironment, restoring impaired microglial process convergence and increasing P2RY12 expression, a key marker of homeostatic function, with concomitant attenuation of aberrant neuronal hyperactivity. Astrocyte-specific PD-L1 knockdown produced similar effects, indicating a key role of astrocytic PD-L1 in regulating microglia-neuron interactions. These findings suggest that the glial PD-1/PD-L1 axis functions as a brain-intrinsic regulator of glial homeostasis linked to neuronal dysfunction in AD.

DOI: https://doi.org/10.1126/sciadv.adx0731
Alzheimers Dement. 2026 Sep;22(9): e71823

Cellular transcriptomic signatures underpinning the heterogeneity of depression in Alzheimer's disease.

Michael W Lutz, Zhaohui Man, Ornit Chiba-Falek.

   INTRODUCTION: Late-onset Alzheimer's disease (LOAD) and major depressive disorder (MDD) share genetic etiologies. Here, we investigated brain transcriptomic landscapes to gain insights into shared and divergent molecular and biological etiologies across LOAD and MDD.
METHODS: Brain single-nucleus RNA sequencing (snRNA-seq) datasets from cognitively normal older and young individuals and LOAD patients stratified by comorbid MDD were analyzed to identify differential expressed genes (DEGs). Using cell type-specific DEGs we performed biological pathway and intercellular-communication networks analyses. We investigated shared DEGs across MDD and LOAD cohorts and sex-specific DEGs. Results were validated by comparison with four transcriptomic and proteomic studies of MDD and depression.
RESULTS: MDD-associated dysregulated genes and pathways were shared between LOAD and cognitive-normal individuals, including JUNB and DUSP1 in glutamatergic neurons, and PRAM1 and SNX9 in microglia. DEGs shared between the MDD and LOAD cohorts included HSPA1A and NDUFB7 in glutamatergic neurons. Sex interaction analysis identified numerous new DEGs in the MDD cohorts, whereas there were ≈5 to 10 times more DEGs in female than in male individuals. LOAD and MDD common microglial pathways included neuronal injury, stress, peroxisome proliferator-activated receptor (PPAR) signaling and interferon alpha/beta signaling.
DISCUSSION: LOAD and MDD exhibited common molecular profiles, dysregulated pathways, and cellular communication changes. MDD develops earlier in life, thus, our findings provide a window into early molecular and biological processes preceding LOAD-onset.

Keywords:  Alzheimer's disease; co‐pathologies; disease heterogeneity; disease subtypes; major depressive disorder; multiomics; neuropsychiatric symptoms; single‐cell sequencing; transcriptomics; translational science

DOI:  https://doi.org/10.1002/alz.71823
J Neuroinflammation. 2026 Aug 06. pii: 314. [Epub ahead of print]23(1):

CX3CL1/CX3CR1-dependent microglial phagocytosis of oligodendrocyte precursor cells contributes to sevoflurane-induced myelination impairments in neonatal mice.

Jiangming Lv, Zhangting Xia, Xin Wang, Ping Zhao, Ziyi Wu.

  General anesthesia exposure in early life may disrupt the normal progression of developmental myelination, but the underlying mechanisms remain unclear. Early postnatal microglia in developing white matter exhibit diverse transcriptional and functional states, including a population with pronounced phagocytic activity. This study aims to investigate whether sevoflurane impairs oligodendrocyte myelination by promoting microglial phagocytosis of oligodendrocyte precursor cells (OPCs). Mice received either a single 2-h exposure to 3.3% sevoflurane on postnatal day 2 (P2) or repeated 2-h exposures on P2, P3, and P4. Neurobehavioral tests were used to assess cognitive and fine motor functions. The effects of microglial phagocytosis of OPCs on cerebral myelination were assessed using three-dimensional reconstruction and related biochemical analysis. Our findings indicate that repeated sevoflurane exposure, rather than a single exposure, induced hypomyelination and was associated with persistent cognitive and fine motor deficits. Repeated sevoflurane exposures promoted microglial activation and excessive phagocytosis of OPCs, thereby decreasing the number of oligodendrocytes and impairing developmental myelination. Mechanistically, repeated sevoflurane exposure enhanced CX3CL1/CX3CR1 signaling in neonatal brain tissue. In cultured microglial cells, sevoflurane altered Rac1-related cytoskeletal regulation and increased phagocytic activity. CX3CR1 knockout attenuated the phagocytic ability of microglia and rescued oligodendrocyte myelination and neurobehaviors. This study indicates that CX3CL1/CX3CR1-dependent microglial phagocytosis of OPCs might contribute to sevoflurane-induced myelination impairments in neonatal mice, and provides a potential therapeutic target for preventing anesthesia-induced developmental neurotoxicity.

Keywords:  CX3CL1; CX3CR1; Developmental neurotoxicity; Microglia; Oligodendrocyte precursor cell; Rac1; Sevoflurane

DOI:  https://doi.org/10.1186/s12974-026-03997-8
Brain Behav Immun. 2026 Sep 14. pii: S0889-1591(26)00758-0. [Epub ahead of print] 107010

DREADDs-Gi mediated inhibition of myeloid cells leads to anti-inflammatory signalling, shrinkage of microglia and acute heart failure in Cx3cr1Cre mice.

Frederik Holde, Tina Myhre Pedersen, Sofie Let Frandsen, Bjarke Thomsen, Vladimir Matchkov, Anna Mathia Klawonn.

  Little is known about the functional consequences of real-time changes to innate immune-cell states. While chemogenetic tools have become increasingly used for probing immune-brain interactions, the consequences of manipulating myeloid cell activity states remain poorly understood. In this study, we found that acute activation of Gi-coupled DREADDs (hM4Di) in Cx3cr1⁺ myeloid cells severely supresses cardiac function and induces a predominantly anti-inflammatory signalling state in mice. This surprising finding prompted further investigation. Using high-resolution ultrasound and electrocardiography, we show that although Cx3cr1⁺ mice have some reduced cardiac function already prior intervention, activation of hM4Di in Cx3cr1+ cells markedly reduces cardiac output and ejection fraction, and induces arrhythmias and increased heart-rate variability, which is absent in Cx3cr1Cre controls. hM4Di activation leads to decreased soma size, but not number, of IBA1⁺ microglia in the hypothalamus, while sections containing nucleus of the solitary tract remained unaffected. Plasma proteomic profiling using the Olink Mouse Exploratory panel revealed increased IL-10 alongside reductions in IL-23R and CCL20, indicating a shift toward systemic anti-inflammatory signalling. Furthermore, Olink analysis revealed a complex systemic signalling profile characterized by changes in several proteins associated with extracellular matrix remodelling, vascular regulation, and cell death pathways. Collectively, these findings demonstrate that Gi-DREADD inhibition of Cx3cr1⁺ myeloid cells produce coordinated central and peripheral immune changes and causes fatal cardiac dysfunction.

Keywords:  Cardiac failure; Cx3cr1+ myeloid cells; Cytokines; DREADDs; Macrophages; Microglia

DOI:  https://doi.org/10.1016/j.bbi.2026.107010
Neurotherapeutics. 2026 Sep 18. pii: S1878-7479(26)00252-7. [Epub ahead of print]23(6): e01082

NEMO (IKKγ) citrullination in microglia promotes neuroinflammation in the post-ischemic brain.

Sang-A Oh, Song-I Seol, Ja-Kyeong Lee, Il-Doo Kim.

  Peptidylarginine deiminase (PAD) catalyzes the post-translational conversion of positively charged arginine residues into neutral citrulline. This modification, known as citrullination, is implicated in various pathological conditions, including those affecting the central nervous system. This study investigated the pro-inflammatory role of PAD in microglia using a middle cerebral artery occlusion (MCAO) animal model of ischemic stroke. Pharmacological inhibition of PAD via BB-Cl-amidine (BBCA; a pan-PAD inhibitor) exerted robust anti-inflammatory and neuroprotective effects in the post-ischemic brain in a broad therapeutic window. A significant accumulation of citrullinated proteins was detected in activated microglia following ischemia, which was suppressed by BBCA. Notably, we demonstrate that citrullination of NEMO (IKKγ), a key regulator that activates the NF-κB signaling pathway, was significantly induced in the post-ischemic brain, facilitating NEMO-IKKα/IKKβ assembly. Importantly, BBCA inhibited NEMO citrullination and disrupted subsequent IKK assembly, highlighting the critical role of PAD in this process. Targeted knockdown experiments using siRNA in BV2 microglial cells revealed that both PAD2 and PAD4 play crucial role in NEMO citrullination and NF-κB-mediated pro-inflammatory response. Furthermore, inhibiting NEMO citrullination with a NEMO-binding domain peptide (NBDp) or co-treatment with NBDp and BBCA, further supports a crucial role for PAD-mediated NEMO citrullination in post-ischemic neuroinflammation. Collectively, these results suggest that PAD2 and PAD4 drive pro-inflammatory processes following cerebral ischemia by upregulating NEMO citrullination and subsequent IKK complex formation.

Keywords:  Inflammation; MCAO; Microglia; NEMO; PAD4

DOI:  https://doi.org/10.1016/j.neurot.2026.e01082
Front Immunol. 2026 ;17 1864888

Microglial dectin-1/Clec7a in an alzheimer's disease model: a double-edged sword across the lifespan.

Wen Xi, Ramona M Rodriguiz, William C Wetsel, Mari L Shinohara.

   Introduction: Dectin-1, encoded by Clec7a, is highly expressed in disease-associated microglia in Alzheimer's disease (AD), yet its in vivo function remains largely unknown.
Methods: We generated Clec7a-floxed mice and conditionally deleted dectin-1 in microglia to determine its effects on pathology and behavior using the 5xFAD mice model. No dectin-1 ligand injection was used. Amyloid pathology, immune phenotypes in the brain, and behavior were examined across disease stages.
Results: In 6-month (mo) old mice, microglial dectin-1 reduced dense Aβ plaques in the subiculum without detectable behavioral effects. At 9-mo, microglial dectin-1 impaired memory retention and spatial learning, accompanied by an increased diffuse/dense Aβ plaque ratio in the hilus of the dentate gyrus and limited brain infiltration of Ly6Glo neutrophils. At 16-mo, microglial dectin-1 increased freezing behavior suggestive of heightened emotional reactivity.
Discussion: Microglial dectin-1 exerts age-dependent effects: beneficial for amyloid pathology in mid-life but detrimental for cognition and anxiety-related behavior in later life. These context-specific outcomes highlight the need to consider age, the cell types expressing dectin-1, and dectin-1-activating ligands. Future studies should define the classes of ligands and signaling landscape of microglial dectin-1 across the disease course with the goal of identifying windows where intervention could tilt its function toward sustained neuroprotection.

Keywords:  5xFAD; alzheimer’s disease; cognitive impairment; dectin-1; fear conditioning; microglia; morris water maze (MWM); mouse behavior assessment

DOI:  https://doi.org/10.3389/fimmu.2026.1864888
iScience. 2026 Sep 18. 29(9): 117412

Transcriptomic landscape of microglia in mouse models of social dysfunction and oxytocin-mediated recovery.

Masafumi Tsurutani, Haruaki Sato, Mitsue Hagihara, Dooseon Cho, Mitsutaka Kadota, Takefumi Kondo, Kazunari Miyamichi.

  Atypical sociability is a hallmark of neurodevelopmental disorders arising from genetic susceptibility and prenatal environmental perturbations that can affect diverse brain cell types. Using single-cell transcriptomics, we previously identified selective vulnerability of parvocellular oxytocin (OT) neurons in the paraventricular hypothalamus (PVH) following embryonic exposure to valproic acid (VPA), a teratogen that induces social deficits. Neonatal chemogenetic activation of OT neurons rescued these behavioral abnormalities and partially restored dysregulated gene expression. However, the effects of VPA exposure and OT neuron stimulation on non-neuronal PVH cells remained unclear. Here, we show that VPA induces transcriptional abnormalities in PVH microglia. Spatial transcriptomics revealed altered distributions of PVH microglial subtypes. Notably, neonatal OT neuron stimulation reversed a subset of VPA-induced microglial gene downregulation, while pharmacological manipulation of microglia normalized aberrant OT gene expression in putative parvocellular OT neurons. These findings support bidirectional OT neuron-microglia interactions that may underlie social dysfunction following embryonic VPA exposure.

Keywords:  autism spectrum disorder; microglia; oxytocin neurons; single-cell transcriptomics; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2026.117412
Int J Mol Sci. 2026 Sep 03. pii: 7870. [Epub ahead of print]27(17):

Let-7a-5p/SHIP-1 Axis Drives SARS-CoV-2 Spike-1-Induced Microglial Pyroptosis.

Puja Pawar, Shraddha Ratnakar, Vandana Saxena.

  Although persistent neurological sequelae in long COVID are reportedly well associated with neuroinflammation, the underlying regulatory mechanisms remain poorly characterized. Previously, we identified dysregulated microRNA expression, including let-7a-5p, in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike S1-stimulated human microglial cells by RNA sequencing; however, how let-7a-5p regulates the S1-mediated neuroinflammatory processes remains undetermined. In the present study, we examined the functional role of let-7a-5p in alleviating S1-induced microglial inflammation in the CHME3 cell line as well as in human monocyte-derived microglia (MDMi) using a loss- and gain-of-function approach. Functional inhibition of let-7a-5p resulted in mitigating S1-induced inflammatory cytokine release and markers of pyroptosis. Mechanistically, we established SHIP-1 as a direct target of let-7a-5p using luciferase reporter assay validation. Interestingly, we noted upregulated expression of the TLR3 gene alongside TLR2/4 in S1-stimulated microglia. Although we could not establish exactly how TLR3 is stimulated in S1-induced neuroinflammatory processes, using siRNA-mediated inhibition and a pharmacological inhibitor in both CHME3 cells and MDMi, our study certainly provides evidence of TLR3 involvement during S1-induced microglial inflammation, which needs further investigation. Together, these in vitro findings demonstrate that the let-7a-5p/SHIP-1 axis regulates S1-induced inflammatory cascades in CHME3 and MDMi cells, providing mechanistic insight into its role in SARS-CoV-2-associated neuroinflammation and warranting further validation in appropriate in vivo/organoid models.

Keywords:  SARS-CoV-2 spike; let-7a-5p/SHIP-1; microglia; neuroinflammation; pyroptosis

DOI:  https://doi.org/10.3390/ijms27177870
Bioorg Chem. 2026 Sep 10. pii: S0045-2068(26)01044-8. [Epub ahead of print]182 110508

AI-guided discovery of a brain-penetrant LILRB4 inhibitor active in microglial and 5xFAD models of Alzheimer's disease.

Somaya A Abdel-Rahman, Moustafa T Gabr.

  The inhibitory microglial receptor LILRB4 (ILT3) suppresses amyloid-β (Aβ) clearance in Alzheimer's disease (AD) through ApoE-dependent signaling. Here, we report an independent artificial intelligence-guided approach for discovering small-molecule inhibitors of the LILRB4-ApoE interaction. Ultralarge-scale screening of approximately 500 million compounds identified chemically distinct molecules that bind LILRB4 with nanomolar affinity and inhibit ApoE engagement, as validated using orthogonal biophysical and biochemical assays. Structural modeling and mutational analysis defined an interdomain pocket and key residues associated with ligand recognition. In human induced pluripotent stem cell-derived microglia, compound 4 reduced SHP1/2 phosphorylation, attenuated NF-κB activation and IL-1β secretion, and restored Aβ uptake without compromising cell viability. The compound exhibited oral bioavailability and brain penetration. In male and female 5xFAD mice, once-daily oral administration improved Y-maze performance and reduced regional Aβ42 levels, inflammatory cytokines, and CD86-positive microglia. These findings establish retrieval-based artificial intelligence as a complementary route to LILRB4 ligand discovery and identify compound 4 as a pharmacologically differentiated candidate for further optimization.

Keywords:  Alzheimer's disease; Drug discovery; ILT3; LILRB4; Small molecules

DOI:  https://doi.org/10.1016/j.bioorg.2026.110508
Proteomics. 2026 Sep 14. e70178

Microglia Ablation and Downstream Effects in the Cerebrospinal Fluid Proteome.

Sinja Buchner, Sihui Song, Stephan A Müller, Yun Chen, Samira Parhizkar, Stefan F Lichtenthaler, David M Holtzman, Mathias Jucker, Stephan A Kaeser.

  Disease-related activation of glial cells leads to changes in the cerebrospinal fluid (CSF) proteome. However, assigning such protein changes to their cellular origins is often difficult. Here, we used microglia (and macrophage) depletion in mice to identify CSF proteins of microglial origin. Young mice were treated with an inhibitor of the colony-stimulating factor 1 receptor, resulting in an almost complete ablation of microglial cells (and brain macrophages). Depleting microglia revealed profound changes in the CSF proteome. Nineteen proteins showed an overall reduction of at least 90%, suggesting a direct microglial or macrophage origin. Strikingly, we also observed an increase in many neuronal and synaptic proteins, likely reflecting compensatory neural changes including the accumulation of certain neuronal proteins that normally act as ligands for receptors on microglia cells, such as fractalkine or interleukin-34. In contrast to the robust changes in microglial and neuronal proteins, there was no evidence of astrogliosis after microglia ablation as determined by proteome analysis and brain histology. These observations are crucial for interpreting changes to the CSF proteome in relation to neuroinflammatory changes in neurological diseases.

Keywords:  CSF proteome; PLX3397; microglia; microglia depletion; pexidartinib

DOI:  https://doi.org/10.1002/pmic.70178
Neurobiol Aging. 2026 Sep 02. pii: S0197-4580(26)00146-6. [Epub ahead of print]169 13-26

Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement.

Georgia L Nolt, Steven M MacLean, Lesley R Golden, Shealee P Thorpe, Isaiah O Stephens, Jessica L Funnell, Chesney R Brock, Chloe C Lucido, Lily Smith, Gabriela Hernandez, Jose M Arbones-Mainar, Cecily Wood, Josh M Morganti, Lance A Johnson.

  Apolipoprotein E (APOE) genotype is the strongest genetic determinant of late-onset Alzheimer's disease (AD) risk. Of its three common isoforms, E4 increases AD risk and promotes inflammatory and metabolic dysregulation, whereas E2 is protective and is associated with altered lipid handling and immune function. Microglia express APOE in response to stress or injury and exhibit isoform-dependent transcriptional profiles, but the specific contribution of microglial APOE to these phenotypes remains unclear. Here, we used an inducible APOE "switch" model to selectively replace microglial E4 with E2 in older adult mice while maintaining E4 expression in other CNS and peripheral cells. Following a Western diet, microglial E2 replacement was associated with fewer phago-lysosomal microglia and decreased apoE localization within these phago-lysosomal microglia. Following a peripheral inflammatory stimulus (LPS), microglial E2 replacement was linked with increased expression of metabolic and immune-related pathways. Together, these findings indicate that microglial E2 expression is associated with selective cellular and transcriptional changes while E4 continues to be expressed by other cell types.

Keywords:  Aging; Apolipoprotein E; Metabolism; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1016/j.neurobiolaging.2026.08.005
J Neuroimmune Pharmacol. 2026 Sep 12. pii: 47. [Epub ahead of print]21(1):

ELAVL3 Exacerbates Brain Injury and Cognitive Dysfunction in Mice After Cardiac Arrest by Increasing S100B mRNA Stability to Promote Microglia Activation.

XueQin Ji, Yan Xia, Yuan Zhao, Yang Wu, Peng Zhang.

   BACKGROUND AND AIMS: Microglial activation-driven neuroinflammation exacerbates secondary brain injury following cerebral ischemia/reperfusion (I/R). The underlying molecular regulators are not fully elucidated. We investigated the role of the RNA-binding protein ELAVL3 and its target S100B in post-ischemic microglial activation and subsequent neuronal injury.
METHODS: In vitro, BV-2 microglia were subjected to oxygen-glucose deprivation/reperfusion (OGD/R), and their conditioned medium was applied to HT22 neurons. In vivo, a mouse model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR) was utilized. Gene expression was modulated using small interfering RNA (siRNA), plasmids, and lentiviral vectors. The ELAVL3-S100B mRNA interaction was confirmed by RNA immunoprecipitation and luciferase assays. Neuronal injury, neuroinflammation, and cognitive outcomes were evaluated using molecular, histological, and behavioral analyses.
RESULTS: OGD/R induced pro-inflammatory activation in microglia, leading to neuronal apoptosis, oxidative stress, and mitochondrial damage. ELAVL3 and S100B were upregulated in activated microglia in vitro and in the hippocampus after CA/CPR. ELAVL3 directly bound the S100B 3'-untranslated region, enhancing its mRNA stability and protein expression. In vitro, ELAVL3 knockdown suppressed S100B, attenuated microglial activation, and protected neurons. In vivo, hippocampal knockdown of either ELAVL3 or S100B reduced neuroinflammation and improved cognitive function after CA/CPR. The neuroprotective effects of ELAVL3 knockdown were rescued by S100B overexpression.
CONCLUSION: Our study identifies the ELAVL3/S100B axis as a key driver of post-ischemic neuroinflammation. ELAVL3 enhances S100B expression post-transcriptionally, promoting microglial-mediated neurotoxicity. Targeting this pathway may offer a potential therapeutic strategy for cerebral ischemic injuries.

Keywords:  Cerebral ischemia/reperfusion; ELAVL3; Microglial activation; Neuroinflammation; S100B; Secondary brain injury

DOI:  https://doi.org/10.1007/s11481-026-10315-9
Invest Ophthalmol Vis Sci. 2026 Sep 01. 67(11): 37

Multiomic Integration Reveals Novel miRNA-mRNA-Protein Expression Profile in the Aged Female Retina.

Nicholas W Bariesheff, Yvette Wooff, Daniel G Blackmore, Adrian V Cioanca.

Purpose: Aging is a leading risk factor for retinal degeneration. MicroRNAs (miRNAs) regulate posttranscriptional gene suppressors and influence inflammation and oxidative stress, two processes disrupted during retinal aging. This study aimed to identify age-related miRNA-mRNA-protein associations between young and older retinas and uncover dysregulated pathways that may contribute to retinal degeneration.
Methods: Retinal function was assessed using electroretinography (ERG), and microgliosis was quantified by microglial immunohistochemistry (IHC). A multiomics approach was used to examine molecular changes in older (30-month-old) female C57BL/6J mouse retinas and compared with young female (3-month-old) controls. Illumina sequencing profiled short miRNAs (20 bp) and bulk mRNAs (150 bp), while total proteomics via mass spectrometry assessed protein expression. Bioinformatic analyses included targetome analysis (miRNet), pathway enrichment (Gene Ontology), and clustering to identify age-associated molecular targets and pathways.
Results: Retinas from older mice displayed neuronal dysfunction and increased microgliosis. Sequencing revealed significant dysregulation of miRNAs linked to immune and inflammatory pathways, supported by enrichment of their predicted mRNA targets. In the older mice, mRNA expression showed broad inflammatory activation, though only 14% of dysregulated mRNAs overlapped with predicted miRNA targets. Proteomic profiling revealed a disconnect between RNA and protein expression, yet all omics layers showed enrichment in inflammatory pathways. Integrated analysis identified associations involving several gene regulatory networks in the older retina.
Conclusions: This study demonstrates that at an advanced age, miRNA expression and their predicted downstream regulatory networks are dysregulated, highlighting potential molecular mechanisms underlying age-related retinal degeneration.

DOI: https://doi.org/10.1167/iovs.67.11.37
Biochem Biophys Res Commun. 2026 Sep 16. pii: S0006-291X(26)01362-8. [Epub ahead of print]837 154596

Transcriptional changes in microglial Kcnk2 during fear memory reconsolidation and TREK-1-associated regulation of TNF-α invitro.

Runen Cheng, Mai Sakai, Sayako Kanno, Mana Nemoto, Chiaki Ono, Yoshie Kikuchi, Mizuki Hino, Yasuto Kunii, Hiroshi Komatsu, Saya Kikuchi, Motoko Maekawa, Yuji Owada, Takaaki Abe, Hiroaki Tomita, Zhiqian Yu.

  Fear memory is associated with microglial tumor necrosis factor-alpha (TNF-α) production; however, the potassium (K+) channel-related mechanisms underlying microglial TNF-α regulation remain incompletely understood. Using in silico reanalysis of a whole-brain microglial microarray dataset obtained after contextual fear conditioning, we identified 20 K+ channel-related transcripts altered during fear memory reconsolidation, including Tnf. Promoter motif enrichment analysis revealed a shared GC-rich regulatory signature among these genes. During reconsolidation, Tnf and Kcnk2 (encoding the two-pore domain K+ channel TREK-1) transcripts were significantly increased in microglia isolated from the prefrontal cortex and hippocampus, accompanied by reduced microglial K+ levels. Furthermore, hippocampal microglial Tnf expression was positively correlated with Kcnk2 expression during reconsolidation. To investigate the potential association between TREK-1-related signaling and microglial TNF-α responses, in vitro mechanistic analyses were performed. TREK-1 knockdown significantly reduced TNF-α production in primary CD11b+ microglia. Pharmacological inhibition of TREK-1 with Spadin decreased basal and lipopolysaccharide-induced TNF-α production, whereas activation with LPS2336 increased TNF-α levels in BV-2 microglial cells. Reduction of extracellular K+ concentrations enhanced TNF-α production in BV-2 cells, an effect attenuated by TREK-1 inhibition. In contrast, comparable TREK-1-associated regulation was not observed in J774.1 macrophages, suggesting a microglia-specific mechanism under the present in vitro conditions. Collectively, these findings identify coordinated alterations in microglial Kcnk2, Tnf, and K+ levels during fear memory reconsolidation and demonstrate TREK-1-associated regulation of TNF-α production in microglia in vitro.

Keywords:  Fear memory; Ionomics analyses; Potassium (K(+)); TNF-α; TREK-1 (Kcnk2)

DOI:  https://doi.org/10.1016/j.bbrc.2026.154596