bims-microg 2026-10-11 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–10–11
seventeen papers selected by
Marcus Karlstetter, Universität zu Köln

Human microglia clear intraneuronal α-synuclein aggregates by GPNMB-mediated trogocytosis.
CYTIP promotes pro-inflammatory activation of microglia through interaction with LRRFIP2 following ischemic stroke.
Early-Life Manganese Overexposure Activates Microglial Phagocytosis through the YY1/TREM2 Axis Leading to Hippocampal Synaptic Remodeling in Mice.
Sequential modulation of the cGAS-STING pathway promotes spinal cord injury repair.
SAMHD1 dysfunction drives microglial phagocytosis of PS-exposing vulnerable neurons via the GAS6-AXL axis in Aicardi-Goutières syndrome.
Stem cells redirect the neuroinflammatory trajectory of primed microglia in an ovine chorioamnionitis model.
Microglia-mediated extracellular matrix disruption drives neuronal dysfunction, motor impairments, and sedation following alcohol abuse.
A method for distinguishing and separating retinal microglia from infiltrating macrophages during an ocular inflammatory event.
AgomiR-31-5p ameliorates diabetes-associated cognitive impairment by suppressing hippocampal neuroinflammation via RAGE-associated signaling.
CAR-engineered microglia harness phagocytosis to target brain tumor in organoid models.
miR-214-3p and NCKAP1: A microglial functional dimension of Alzheimer's progression.
Dendrimer Delivered shRNA Targeting the CCL20-CCR6 Axis Suppresses Complement-Mediated Microglial Synaptic Pruning and Ameliorates Chronic Neuroinflammation After Repetitive Traumatic Brain Injury.
Targeting C3aR/STAT3 signaling attenuates neuroinflammation and reverses neurological impairment in Neuromyelitis optica.
Sonic Hedgehog Protects Against Ischemic Brain Injury Via Modulating DRP1-Dependent Microglial Pyroptosis.
Dynamic effects of microglial NLRP3 on transcriptional alterations post-traumatic brain injury.
C1qc Mediates Blood-Brain Barrier Disruption in a Mouse Model of Intracerebral Haemorrhage Through Microglia-Derived Migrasomes.
Inducible human yolk sac myeloid progenitors model myeloid ontogeny and enable tissue-resident macrophage replacement in vivo.

Sci Transl Med. 2026 Oct 07. 18(870): eadz9258

Human microglia clear intraneuronal α-synuclein aggregates by GPNMB-mediated trogocytosis.

Hung-Ju Chueh, Antigoni Katsikoudi, Ana Aragón-González, Chor Lai Lam, Liezel Tamon, Ashwin Jainarayanan, Devika Agarwal, Sally A Cowley, David Sims, George K Tofaris.

Microglia are the primary immune cells of the brain, but their role in Parkinson's disease is not fully understood. Chronic microglial activation is toxic to neurons, but in the early stages of pathology, microglia also exert beneficial functions. We used induced pluripotent stem cell (iPSC)-derived coculture models to investigate how human microglia respond to α-synuclein aggregates that form de novo inside human dopaminergic neurons with α-synuclein gene triplication or are triggered by fibrils. We found that microglia cleared Ser129-phosphorylated α-synuclein aggregates through a contact-dependent mechanism. This process was fine-tuned by sensing (P2RY12) and inhibitory (CD22) signals and involved selective phagocytosis of neuronal subcompartments (trogocytosis), independently of TREM2 or phosphatidylserine. In the presence of intraneuronal α-synuclein aggregates, microglia exhibited morphological and transcriptional changes indicative of activation. Using single-cell sequencing, we identified a cluster of disease-associated microglia (DAM) responsible for this beneficial phenotype and the Parkinson's disease GWAS candidate glycoprotein nonmetastatic melanoma protein B (GPNMB) as a key effector of aggregate clearance by microglial lysosomes. GPNMB interacted with Ser129-phosphorylated α-synuclein in iPSC-derived microglia exposed to aggregate-laden dopaminergic neurons and was up-regulated in substantia nigra microglia of individuals with incidental Lewy bodies or Parkinson's disease. Microglia-specific GPNMB knockdown using CRISPRi reduced intraneuronal aggregate clearance. GPNMB-mediated trogocytosis was negatively regulated by an autocrine IL-10 signaling loop, whereas IL-10 receptor blockade enhanced the phagocytic response. Together, our study identifies a subtype of human microglia capable of removing intraneuronal aggregates and potential therapeutic targets.

DOI: https://doi.org/10.1126/scitranslmed.adz9258
Cell Signal. 2026 Oct 03. pii: S0898-6568(26)00588-7. [Epub ahead of print] 112929

CYTIP promotes pro-inflammatory activation of microglia through interaction with LRRFIP2 following ischemic stroke.

Zhihao Yang, Yiqi Wang, Yuneng Zhou, Ruolin Zhang, Chang Liu, Wendai Bao, Jun Qin, Peiyang Zhou, Guangqiang Li, Chao Duan, Jiawen Dong, Haipeng Wang, Min Zhang, Xin Yang, Ke Shui, Zhiqiang Dong.

  Microglia-mediated neuroinflammation is a critical contributor to cerebral ischemia/reperfusion (I/R) injury. However, the functional heterogeneity of microglia presents significant challenges in defining therapeutic signatures. By integrating single-nucleus RNA sequencing (snRNA-seq) of a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model with bulk RNA sequencing of BV2 microglia subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), we identified Cytip as a highly upregulated core regulator within a transient "primed" microglial subpopulation upon I/R insult. Functional validation demonstrated that Cytip promotes a pro-inflammatory microglial phenotype and exacerbates oxidative stress, whereas its knockdown ameliorates these OGD/R-induced dysfunctions. Mechanistically, immunoprecipitation-mass spectrometry revealed that CYTIP directly interacts with LRRFIP2. Overexpression of LRRFIP2 counteracted CYTIP-mediated pathogenic effects, significantly suppressing microglial inflammation and IL-1β production. These findings suggest that CYTIP promotes microglial inflammatory responses via the NLRP3/LRRFIP2 axis, highlighting the CYTIP-LRRFIP2 interaction as a promising therapeutic target for post-stroke recovery.

Keywords:  CYTIP; Ischemia and reperfusion; Microglia; Neuroinflammation; Single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.cellsig.2026.112929
Adv Sci (Weinh). 2026 Oct 04. e78036

Early-Life Manganese Overexposure Activates Microglial Phagocytosis through the YY1/TREM2 Axis Leading to Hippocampal Synaptic Remodeling in Mice.

Keyu Chen, Bin He, Kuan Liu, Zhuo Ma, Bin Xu.

  The early-stage hippocampal development depends on precise synaptic remodeling, processes where microglia play indispensable roles. Disruption of this event reshape hippocampal neural circuit architecture and heighten the risk for long-term memory, learning, and behavioral deficits. Manganese (Mn), a widespread environmental contaminant, is recognized for neurodevelopmental toxicity and reported disrupting hippocampal synaptic integrity. Here, we report that early-life Mn exposure impaired learning, long-term memory, and behavioral performance in young adulthood male mice, accompanied by microglia excessive-phagocytosis and aberrant hippocampal synaptic remodeling. Single-nucleus transcriptomics, CUT&Tag profiling collectively reveal that Mn exposure elevated the transcription factor Yin Yang 1 (YY1) expression in developing microglia and directly activated transcription of triggering receptor expressed on myeloid cells 2 (TREM2) and phagolysosomal pathway-related genes, thereby driving excessive microglial phagocytosis. This heightened engulfment capacity led to over-phagocytosis ultimately resulting in abnormal synaptic remodeling during critical developmental windows. Mechanistically, Mn-induced YY1 accumulation may result from enhanced HIF1α-mediated transcription and disrupted SMURF2-dependent ubiquitin degradation. Together, our findings identified YY1/TREM2 as an axis through which early-life Mn exposure perturbed microglial homeostasis and induced maladaptive synaptic remodeling. These results provide mechanistic insight into neurodevelopmental consequences of Mn exposure and highlight potential molecular targets for potential early therapeutic intervention of neurological disorders.

Keywords:  hippocampal development; microglial phagocytosis; neurological disorders; triggering receptor expressed on myeloid cells 2 (TREM2); yin yang 1 (YY1)

DOI:  https://doi.org/10.1002/advs.78036
J Adv Res. 2026 Oct 09. pii: S2090-1232(26)00784-8. [Epub ahead of print]

Sequential modulation of the cGAS-STING pathway promotes spinal cord injury repair.

Qianqian Peng, Ling Luo, Min Yuan, Hui Li, Lü Chen, Xin Wu, Maolin Han, Shirong Wen, Changlai Zhu, Yun Gu.

   INTRODUCTION: The cGAS-STING pathway is a central innate immune sensor of cytosolic DNA. Spinal cord injury (SCI) triggers sterile inflammation, but the spatiotemporal role of this pathway in injured spinal cord repair remains unclear. Understanding its phase-dependent functions may enable precise immunomodulation to improve recovery.
OBJECTIVES: This study aimed to investigate the dynamic activation of the cGAS-STING pathway after SCI and to determine whether a time-sequenced pharmacological strategy, consisting of early activation followed by late inhibition, could enhance functional repair.
METHODS: A mouse thoracic compressive SCI model was used. Pathway expression and cellular localization were assessed by western blot, immunofluorescence, and transcriptomics. Sustained or sequential modulation was performed using STING agonists and antagonists. Motor recovery was evaluated by the Basso Mouse Scale and footprint analysis. Axonal integrity, myelin preservation, and glial scarring were analyzed histologically. Myeloid cells (including microglia) were depleted with PLX5622, and neuron-microglia cocultures were established for mechanistic studies.
RESULTS: cGAS-STING was significantly activated predominantly in myeloid cells (mainly microglia, with a smaller contribution from infiltrating macrophages) after SCI. Sustained activation or inhibition failed to improve recovery. Sequential treatment (ADU-S100 days 0-10 → C-176 days 11-28) markedly enhanced motor function, axonal integrity, and myelin preservation while reducing glial scarring. Mechanistically, early activation boosted microglial phagocytosis and clearance; late inhibition resolved inflammation and promoted the expression of anti-inflammatory and axon-associated genes. Myeloid cell depletion completely abolished these benefits.
CONCLUSION: The cGAS-STING pathway exerts phase‑dependent, biphasic functions in SCI. A precisely timed "activation followed by inhibition" strategy optimally harnesses myeloid cell dynamics to coordinate debris clearance and inflammation resolution, offering a novel immunomodulatory paradigm for central nervous system repair.

Keywords:  Chrono-immunomodulation; Microglia; Neuroinflammation; Sequential drug regimen; Spinal cord injury; cGAS-STING

DOI:  https://doi.org/10.1016/j.jare.2026.10.023
Exp Neurol. 2026 Oct 08. pii: S0014-4886(26)00424-3. [Epub ahead of print] 116057

SAMHD1 dysfunction drives microglial phagocytosis of PS-exposing vulnerable neurons via the GAS6-AXL axis in Aicardi-Goutières syndrome.

Jiuhao Cui, Ziyang Shen, Hancheng Liu, Ting Chen, Ling Zhang, Junhong Jiang, Li Yang, De Wu, Songcheng Ying.

  SAMHD1 mutations can cause Aicardi-Goutières syndrome (AGS), a severe inflammatory encephalopathy characterized by progressive brain atrophy. To date, the molecular and cellular mechanisms linking SAMHD1 dysfunction to brain atrophy remain poorly understood. In this study, we found that SAMHD1 deficiency increased neuronal apoptosis and reduced neuronal density in the hippocampal region of Samhd1 knockout rats. In vitro, SAMHD1 knockdown in HMC3 microglia significantly enhanced phagocytic capacity, including uptake of fluorescent microspheres, apoptotic neurons, and remarkably live neurons, as visualized by pHrodo labeling and live-cell imaging. Transwell co-culture experiments revealed that SAMHD1-deficient microglia induced phosphatidylserine (PS) exposure on the surface of viable neurons, upregulating pro-phagocytic ("eat-me") signals while downregulating anti-phagocytic ("don't-eat-me") signals. Transcriptomic analysis identified GAS6 as a key upregulated molecule in SAMHD1-dysfunctional microglia. Knockdown of GAS6 or pharmacological inhibition of its receptor AXL abrogated the enhanced phagocytosis of PS-exposing neurons, establishing the functional requirement of the GAS6-AXL axis. Furthermore, SAMHD1 knockdown could activate downstream PI3K/AKT signaling, and both GAS6 silencing and AXL inhibition suppressed PI3K and AKT phosphorylation. Collectively, we demonstrate that SAMHD1 dysfunction drives aberrant microglial phagocytosis of PS-exposing vulnerable neurons potentially through the GAS6-AXL-PI3K/AKT signaling axis, providing a potential mechanistic basis and therapeutic target for brain atrophy in AGS.

Keywords:  Aicardi–Goutières syndrome; GAS6-AXL axis; Live neuron phagocytosis; Microglia; SAMHD1

DOI:  https://doi.org/10.1016/j.expneurol.2026.116057
Brain Behav Immun Health. 2026 Nov;57 101359

Stem cells redirect the neuroinflammatory trajectory of primed microglia in an ovine chorioamnionitis model.

Valéry L E van Bruggen, Sanne J C M Claassen, Luise Klein, Cindy Bokobza, Jennifer Hua, Tiphaine Marvillet, Michelle M E Zandbergen, Charlotte van Gorp, Florian Caimant, Renate G van der Molen, Pierre Gressens, Daan R M G Ophelders, Tim G A M Wolfs.

  Antenatal infection (e.g. chorioamnionitis), an important risk factor for preterm birth, can induce a fetal systemic inflammatory response (FIRS), initiating neuroinflammation. Microglia, as principal resident immune cells of the brain, are key targets for therapeutic interventions such as Multipotent adult progenitor cells (MAPC). We analyzed the effects of intravenous MAPC therapy on microglia and peripheral immune cells at the blood-brain barrier (BBB) in an ovine chorioamnionitis model. Ovine fetuses were intra-amniotic (i.a.) exposed to lipopolysaccharide (LPS) to induce FIRS, or saline (SAL) at 125 days gestational age (dGA), followed by intravenous MAPC therapy or SAL at 127 dGA. After sacrifice (132 dGA), isolated microglia were analyzed by qRT-PCR and RNA sequencing. Microglial function was assessed through efferocytosis of Jurkat cells. Additionally, immunohistochemistry of immune cells (CD45, IBA-1, MPO) and their ANXA1 co-expression were quantified in brain parenchyma and BBB. Antenatal inflammation resulted in an increased efferocytotic capacity following in vitro LPS re-exposure and gene ontology annotations revealed significant changes in immunomodulatory genes, indicating microglial priming. This was further confirmed through selective upregulation of IL-10 and ANXA1, accompanied by increased COX-2 in MAPC-treated animals following i.a. LPS exposure. This was paralleled by increased numbers of ANXA1+ immune cells at the BBB and brain parenchyma. Microglial RNA transcriptomic analysis underlined the immunomodulatory and postulated neuroprotective effects of MAPC therapy. We conclude that antenatal inflammation primes microglia which can be targeted by MAPC therapy. Early redirection of neuroinflammation may preserve neural integrity and prevent subsequent neurocognitive impairments in later life.

Keywords:  Chorioamnionitis; Microglia; Neuroinflammation; Ovine model; Preterm brain injury; Stem cell therapy

DOI:  https://doi.org/10.1016/j.bbih.2026.101359
Immunity. 2026 Oct 08. pii: S1074-7613(26)00386-9. [Epub ahead of print]

Microglia-mediated extracellular matrix disruption drives neuronal dysfunction, motor impairments, and sedation following alcohol abuse.

Evi Paouri, Sarah Stanko, Nadia Gasmi, Gabriele Glusauskas, Valery Mao, Andrew Kwak, Stephanie Hsu, Sahar Sarmadi, Emily Huang, Aniruddha Das, Courtney Hershberger, Quinn Watercutter, Megan R McMullen, Christopher Birck, Hope Burton, Hale Tobin, Anxhela Gjojdeshi, Julia Dziabis, Richa M Hanamsagar, Daniel M Rotroff, Richard A Prayson, Staci D Bilbo, Saba Valadkhan, Hod Dana, Laura E Nagy, Dimitrios Davalos.

  Alcohol abuse is the primary risk factor for alcohol use disorder (AUD), a leading cause of preventable morbidity and mortality worldwide. While direct effects of alcohol on neuronal function are well established, the role of microglia in acute and chronic neurological dysfunction in AUD remains underappreciated. Using mouse models of binge and high-intensity alcohol exposure and longitudinal in vivo imaging, we found that microglia exhibited acute and progressive morphological responses that preceded but paralleled ethanol-induced sedation. Ethanol also induced microglia-dependent extracellular matrix (ECM) disruption, synapse elimination, and reduced neuronal activity and density. Genetic deletion of microglial Myd88 protected against ethanol-induced microglial reactivity, neuronal damage and dysfunction, intoxication, and motor impairments by preventing ECM disruption. Frontal cortex ECM was similarly disrupted in human brain tissue from individuals with AUD. These findings identify microglia as cellular drivers of brain dysfunction following alcohol abuse and MyD88 as a critical therapeutic target for AUD.

Keywords:  MyD88; alcohol abuse; alcohol use disorder; ethanol-induced sedation; extracellular matrix; microglia; neuroinflammation; prefrontal cortex; two-photon imaging

DOI:  https://doi.org/10.1016/j.immuni.2026.09.011
Front Immunol. 2026 ;17 1951506

A method for distinguishing and separating retinal microglia from infiltrating macrophages during an ocular inflammatory event.

Scott W McPherson, Laura Burgstaler, Joe Sherman, Abigail Patin, Heidi Roehrich.

  A significant challenge in the study of neuroimmune responses is the identification and separation of resident microglia from infiltrating bone marrow-derived macrophages. Therefore, we investigated whether dual labelling of Cx3cr1 and Ccr2 is sufficient to discriminate retinal microglia from infiltrating macrophages in mice that develop spontaneous autoimmune uveoretinitis-a condition dependent on infiltration of lymphocytes and antigen presenting cells from the circulation into the retina. Mice expressing red fluorescent protein (RFP) under control of the Ccr2 promoter and green fluorescent protein (GFP) under control of the Cx3cr1 promoter (Ccr2RFPCx3cr1GFP mice) were crossed with the uveitogenic R161H mouse line. Retinas of R161Hneg x Ccr2RFP+/-Cx3cr1GFP+/- F1 mice, including those given an optic nerve crush injury to stimulate retinal MG expansion, and R161H+/- x Ccr2RFP+/-Cx3cr1GFP+/- F1 mice were analyzed for RFP and GFP expressing cells by fundoscopy, flow cytometry, fluorescence microscopy, and for Ccr2 expression by single cell RNA sequencing of retinal CD45+ cells. Retinas from control and optic nerve crushed R161Hneg x Ccr2RFP+/-Cx3cr1GFP+/- F1 mice contained a single population of CD45+ cells expressing a uniquely high level of GFP but were devoid of RFP+ cells, while retinas from R161H+/- x Ccr2RFP+/-Cx3cr1GFP+/- F1 mice had GFPhi cells and increasing amounts of GFPnegRFP+ and GFPlo-medRFP+ cells as uveoretinitis progressed. Thus, dual labelling of Ccr2 and Cx3cr1 can distinguish retinal microglia from infiltrating immune cells, and as GFP+, RFP+, and GFP+RFP+ cells can be easily separated by flow cytometry, our system provides a method for their separation for downstream cellular analysis.

Keywords:  autoimmunity; inflammation; macrophage; microglia; retina

DOI:  https://doi.org/10.3389/fimmu.2026.1951506
Exp Neurol. 2026 Oct 09. pii: S0014-4886(26)00417-6. [Epub ahead of print] 116050

AgomiR-31-5p ameliorates diabetes-associated cognitive impairment by suppressing hippocampal neuroinflammation via RAGE-associated signaling.

Zhiying Zou, Jiahui Zhao, Wanzhen Han, Panpan Meng, Hao Yang, Junxiu Xi, Ting Lei, Wandi Li, Ruohan Shi, Yulin Wang, Xueliang Wang, Mengrou Liu, Qianfa Long.

  Diabetes-associated cognitive impairment is closely linked to hippocampal neuroinflammation, but effective treatments remain limited. This study investigated the protective effects of agomiR-31-5p against cognitive dysfunction and neuroinflammatory injury in db/db mice. Male db/db mice received agomiR-31-5p via tail-vein injection, followed by assessments of cognition, hippocampal microglial activation, synaptic integrity, apoptosis, and inflammatory signaling. AgomiR negative controls were included in the corresponding molecular and cellular experiments. AgomiR-31-5p improved cognitive performance compared with vehicle treatment and attenuated microglial activation, as evidenced by reduced IBA1 and CD68 immunoreactivity, partial normalization of microglial morphology, decreased iNOS expression, and increased IL-10 expression. It also restored PSD95 and SYN expression, reduced the spatial association between microglial and PSD95 signals, and ameliorated apoptosis-related alterations. Molecular docking predicted a potential interaction between agomiR-31-5p and RAGE. In vivo, agomiR-31-5p reduced RAGE expression, p38/ERK/NF-κB signaling activation, and hippocampal TNF-α, IL-6, and IL-1β levels. In high glucose-exposed primary microglia, agomiR-31-5p suppressed inflammatory activation and RAGE/NF-κB signaling. RAGE overexpression partially reversed these effects, supporting the functional involvement of RAGE-associated signaling without establishing RAGE as a direct agomiR-31-5p target. Collectively, agomiR-31-5p may alleviate diabetes-associated cognitive impairment by attenuating microglia-mediated neuroinflammation, preserving synaptic integrity, reducing apoptosis-related injury, and modulating RAGE-associated signaling.

Keywords:  Agomir-31-5p; Diabetes-associated cognitive impairment; Hippocampal neuroinflammation; NF-κB; RAGE

DOI:  https://doi.org/10.1016/j.expneurol.2026.116050
Cell Rep. 2026 Oct 06. pii: S2211-1247(26)01170-8. [Epub ahead of print]45(10): 118091

CAR-engineered microglia harness phagocytosis to target brain tumor in organoid models.

Mu Seog Choe, Woo Sub Yang, Bilal Cakir, Ferdi Ridvan Kiral, Jonghun Kim, Cynthia Lo, Eena Cheng, Benjamin Ongnok, Viswanathan Muthusamy, Nipon Chattipakorn, Siriporn C Chattipakorn, In-Hyun Park.

  Glioblastoma (GBM) is among the most aggressive and lethal brain tumors, and standard treatment offers only modest survival benefits. Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic cancers, but its efficacy in GBM remains limited. Here we develop a CAR-engineered microglia (CAR-MG) platform and an organoid-based framework to test whether programmable microglial phagocytosis can be directed against GBM. We isolate microglia (MG) from human cortical organoids and engineer them to express a CAR targeting EGFRvIII, a recurrent tumor-specific EGFR deletion variant in GBM. In a 2D co-culture, CAR-MG selectively eliminates GBM cells through phagocytosis. In a 3D GBM-cortical organoid model, CAR-MG infiltrates tumor sites and depletes GBM cells over extended culture. Single-cell RNA sequencing (scRNA-seq) shows elevated phagocytic pathways in CAR-MG and detects internalized tumor-derived transcripts, which resolve phagocytosis-resistance programs. These results support CAR-MG as a myeloid CAR modality for human brain organoid models.

Keywords:  CAR-microglia; CP: cancer; CP: neuroscience; EGFRvIII; PU.1; chimeric antigen receptor; cortical organoid; glioblastoma; iPSCs; immunotherapy; microglia; phagocytosis

DOI:  https://doi.org/10.1016/j.celrep.2026.118091
Alzheimers Dement. 2026 Oct;22(10): e71903

miR-214-3p and NCKAP1: A microglial functional dimension of Alzheimer's progression.

Min-Young Noh, Yeonsil Moon, Sungwoo Kang, Won-Jin Moon, Hee-Jin Kim, Sang Won Seo, Sugyeong Ahn, Mi-Hyeon Kang, Yong Sung Kim, Hyunkee Kim, Jae-Sung Bae, Hee Kyung Jin, Hojin Choi, Seong-Ho Koh, Kee Hyung Park, Gregory S Day, Guojun Bu, Seung Hyun Kim.

   INTRODUCTION: Biological Alzheimer's disease (AD) pathology does not fully explain the marked heterogeneity in clinical severity or progression. We investigated whether patient-derived induced microglia-like cell (iMG) profiles capture a functional dimension of AD progression beyond conventional plasma biomarkers.
METHODS: We studied 114 participants comprising amyloid-negative healthy controls (n = 18) and amyloid-positive AD-continuum groups (cognitively unimpaired, n = 2; mild cognitive impairment, n = 18; AD dementia, n = 76). Plasma biomarkers, patient-derived iMG phagocytic function, and molecular markers were measured from the same blood draw. Longitudinal clinical follow-up was available in 102 participants, and paired baseline/follow-up blood samples were analyzed in a longitudinal biomarker cohort (n = 38).
RESULTS: iMG phagocytic capacity progressively declined across the AD continuum, accompanied by reduced NCK-associated protein 1 (NCKAP1) expression and the strongest association with plasma glial fibrillary acidic protein (GFAP). Baseline NCKAP1 primarily reflected current cognitive impairment, whereas plasma miR-214-3p independently predicted faster cognitive decline beyond plasma tau phosphorylated at threonine 217 (p-tau217), GFAP, neurofilament light chain (NfL), age, and baseline cognition. Within amyloid-positive AD dementia, plasma miR-214-3p identified rapidly progressive disease and substantially improved prognostic discrimination beyond conventional plasma biomarkers. Longitudinally, declining NCKAP1 and increasing plasma miR-214-3p tracked the rate of cognitive deterioration, whereas plasma p-tau217, GFAP, and NfL changed over time but did not track disease tempo.
DISCUSSION: Patient-derived iMG profiling identifies microglial phagocytic dysfunction as a complementary functional dimension of AD progression beyond conventional plasma biomarkers. Longitudinal microglial dynamics tracked disease tempo more closely than conventional plasma pathology markers and may help interpret biological-clinical discordance, supporting biologically informed staging, prognosis, and patient stratification in AD.

Keywords:  Alzheimer's disease; NCK‐associated protein 1 (NCKAP1); induced microglia; longitudinal progression; miR‐214‐3p; microglial phagocytic exhaustion; plasma biomarkers

DOI:  https://doi.org/10.1002/alz.71903
Mol Ther. 2026 Oct 09. pii: S1525-0016(26)00858-0. [Epub ahead of print]

Dendrimer Delivered shRNA Targeting the CCL20-CCR6 Axis Suppresses Complement-Mediated Microglial Synaptic Pruning and Ameliorates Chronic Neuroinflammation After Repetitive Traumatic Brain Injury.

Karthick Mayilsamy, Parthvi Bharatkumar Patel, Ryan Green, Sashank Bikkasani, Kristina Tosi, Shreyasi Majumdar, Santosh Kumar Prajapati, Eleni Markoutsa, Tiara Wolf, Jennifer Guergues, Stanley M Stevens, Alison Willing, Shyam Mohapatra, Subhra Mohapatra.

Repetitive traumatic brain injury (rTBI) induces persistent microglial activation and chronic neuroinflammation, yet the upstream signals driving long-term synaptic injury remain unclear. In this study, we identify the CCL20-CCR6 chemokine axis as a critical regulator of sustained microglial activation and complement-dependent synaptic loss after rTBI. Proteomic profiling at 30 days post-injury (dpi) showed broad normalization of complement-linked inflammatory and synaptic pathways in the cortex and hippocampus, underscoring a mechanistic link between chemokine signaling, microglial activation, and synaptic vulnerability. To therapeutically target this axis, we developed a dendrimer-based shRNA platform (shCombo-DPX) that simultaneously silences CCL20 and CCR6. Intranasal and intravenous delivery in rTBI mice effectively reduced CCL20-CCR6 expression, attenuated chronic microgliosis and astrogliosis, and suppressed complement activation. Treatment limited microglial synaptic engulfment, preserved synaptic proteins, restored BDNF levels, and improved motor, anxiety-related, and cognitive outcomes. In microglia-neuron coculture systems, CCL20 silencing reduced LPS-induced complement signaling and prevented synaptic loss, neuronal apoptosis, and BDNF depletion. Conversely, exposure to recombinant CCL20 induced dendritic degeneration, caspase-3 activation, microglial reactivity, complement dysregulation, and synaptic injury both in vitro and in vivo. Collectively, these findings establish CCL20-CCR6 as a key upstream driver of chronic complement-mediated synaptic degeneration after rTBI and support dendrimer-delivered shRNA therapy as a targeted strategy to mitigate long-term neurodegeneration.

DOI: https://doi.org/10.1016/j.ymthe.2026.10.002
Fundam Res. 2026 Sep;6(5): 3491-3506

Targeting C3aR/STAT3 signaling attenuates neuroinflammation and reverses neurological impairment in Neuromyelitis optica.

Li Xu, Xinyi Wang, Huiming Xu, Siqi Chen, Wei Jiang, Haoyang Li, Shabbir Khan Afridi, Yuge Wang, Wenjing Luo, Hui Yang, Changyong Tang, Wei Qiu.

  Abundant evidence indicates that the interaction between astrocytes and microglia through the C3-C3a receptor (C3aR) pathway is a crucial contributor to the pathogenesis of neurodegenerative and autoimmune disorders, such as neuromyelitis optica (NMO). However, the role of C3aR in microglia in modulating inflammation related to local lesions and neurological dysfunctions in NMO remains unclear. In this study, we reveal for the first time that the expression of C3aR on microglia is positively correlated with microglial activation, proinflammatory cytokine secretion, and complement deposition, which results in the typical NMO-like lesion characterized by astrocyte injury with aquaporin 4 (AQP4) loss, demyelination, and motor neuron loss, as well as cognitive impairments, visual defects, and locomotor deficits in different models of NMO. The knockdown of C3aR or the use of a C3aR antagonist, both ex vivo and in vivo, effectively attenuates neuroinflammation, alleviates pathological lesions, and rescues neurological functions. Mechanistically, we identify STAT3 as a downstream target of microglial C3aR signaling that functionally mediates NMO pathogenesis. Blocking the C3aR/STAT3 cascade restores motor and visual functions by reducing the release of proinflammatory factors. Taken together, our study demonstrates a key role of the C3aR-STAT3 pathway in regulating neuroinflammation in NMO pathology and provides potential targets for therapeutic intervention.

Keywords:  C3aR-STAT3 pathway; Microglia; Neuroinflammation; Neurological dysfunction; Neuromyelitis optica (NMO)

DOI:  https://doi.org/10.1016/j.fmre.2025.11.001
Neurochem Res. 2026 Oct 05. pii: 280. [Epub ahead of print]51(5):

Sonic Hedgehog Protects Against Ischemic Brain Injury Via Modulating DRP1-Dependent Microglial Pyroptosis.

Xiaosong Song, Jun Wen, Hao Tang, Lei Yu, Qin Yang.

   BACKGROUND: Microglial pyroptosis plays a critical role in the neuroinflammation following ischemic stroke. Although Sonic Hedgehog (SHH) signaling has been shown to exert neuroprotective effects in cerebral ischemia, whether SHH regulates microglial pyroptosis and the underlying mechanisms remain largely unclear.
METHODS: Serum samples from patients with acute ischemic stroke (AIS) and healthy controls were analyzed using ELISA. Middle cerebral artery occlusion/reperfusion (MCAO/R) mice and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated BV2 microglia were established as in vivo and in vitro ischemic models, respectively. SHH and DRP1 expression were manipulated using adeno-associated virus (AAV)-mediated knockdown or siRNA transfection. Pyroptosis-related molecules were evaluated by qRT-PCR, western blotting, immunofluorescence staining, and scanning electron microscopy. Infarct volume and neurological function were assessed by TTC staining, modified neurological severity score (mNSS), and corner test.
RESULTS: Serum SHH levels were significantly reduced in AIS patients and negatively correlated with circulating inflammatory cytokines. Separately, GEPIA2 analysis of human brain tissue datasets revealed that SHH expression was negatively correlated with the pyroptosis-related genes IL1B, GSDMD, and CASP1. Both in vivo and in vitro ischemic interventions markedly upregulated the expression of SHH, DRP1, and pyroptosis-associated proteins in microglia. SHH knockdown elevated DRP1 expression, aggravated microglial pyroptosis, enlarged cerebral infarct volume, and worsened neurological dysfunction. Rescue experiments confirmed that DRP1 knockdown effectively reversed the pro-pyroptotic and injury-aggravating effects of SHH inhibition in microglia after ischemic stroke.
CONCLUSIONS: SHH protects against cerebral ischemic injury by suppressing DRP1-mediated microglial pyroptosis. The SHH-DRP1 signaling axis represents a previously unrecognized regulatory pathway involved in ischemic stroke and may serve as a potential therapeutic target for limiting neuroinflammation and improving neurological outcomes.

Keywords:  Acute ischemic stroke; DRP1; Neuroinflammation; Pyroptosis; SHH

DOI:  https://doi.org/10.1007/s11064-026-04900-w
Front Neurosci. 2026 ;20 1951885

Dynamic effects of microglial NLRP3 on transcriptional alterations post-traumatic brain injury.

Ruo-Bing Gao, Chang-Hong Li, Nan Yang, Xing Chen, Bo Wang, Dan Xu, Gan Luo, Zi-Jian Yan, Ya-Lei Ning, Hao Du, Yong-Gang Liu.

   Introduction: The nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is predominantly expressed in microglia within the central nervous system (CNS) and plays critical roles in neuroinflammatory diseases, including traumatic brain injury (TBI). The function of the microglial NLRP3 inflammasome may vary as the disease progresses. A comprehensive understanding of these dynamic alterations is essential for opti-mizing the therapeutic time window. Post-TBI, microglial NLRP3 levels exhib-ited significant elevation, and microglial-specific NLRP3 conditional knockout (NLRP3-CKO) reduced neurological and neuropathological impairments.
Methods: Transcriptome sequencing was performed at baseline and on days 1, 3, and 7 post-TBI using injured cortical tissue from NLRP3-CKO mice and their litter-mate controls.
Results: Notable transcriptional changes occurred on day 3 post-TBI, while fewer differentially expressed genes (DEGs) were identified at other time points. NLRP3-CKO influenced macrophage polarization on day 1 and neuronal cell survival on day 3 post-injury. In addition, NLRP3-CKO significantly reduced the upregulation of pyroptosis-related genes and the dysregulation of genes associ-ated with neuroinflammation and neuropathology after TBI. Gene set enrichment analysis (GSEA) indicated diverse potential regulatory pathways at various time points. The temporal profiles of gene expression were also analyzed, revealing distinct expression trends in several gene clusters, particularly on day 7 post-TBI. Pathway enrichment analysis of overlapping genes in these clusters identified several relevant pathways, which were further validated through quantitative real-time polymerase chain reaction (qPCR).
Discussion: Overall, these findings elucidate the dynamic effects of microglial NLRP3 on transcriptomic alterations during the acute phase of TBI and highlight potential regulatory pathways, offering insights into NLRP3 inflammasome-related pathological mechanisms and enhancing the optimization of therapeutic time windows for TBI.

Keywords:  CNS; NLRP3; microglia; transcriptome; traumatic brain injury

DOI:  https://doi.org/10.3389/fnins.2026.1951885
J Extracell Vesicles. 2026 Oct;15(10): e70377

C1qc Mediates Blood-Brain Barrier Disruption in a Mouse Model of Intracerebral Haemorrhage Through Microglia-Derived Migrasomes.

Mengyuan Li, Zhihua Li, Dengpan Song, Fang Wang, Mengzhao Feng, Chi-Tai Yeh, Tingting Zhai, Menghan Deng, Yanyan Sun, Junyang Wang, Xuemei Chen, Yating Wang, Qiong Yang, Moxin Wu, Xiaoping Yin, Junmin Wang, Jian Wang, Fuyou Guo.

  Extracellular vesicles (EVs) are essential for intercellular communication and significantly influence neuroimmune responses after intracerebral haemorrhage (ICH). This study elucidates the immune mechanisms underlying secondary brain injury following ICH by identifying microglia-derived migrasomes. By integrating immune cell clustering analysis from single-cell RNA sequencing (scRNA-seq) with Mendelian randomization, we identified five key genes associated with ICH. Further experiments revealed that C1qc accumulates around hematomas, worsening blood‒brain barrier (BBB) disruption through migrasome-mediated pathways. Our results showed that microglial migrasomes transport C1qc to induce pyroptosis in vascular endothelial cells, thereby compromising BBB integrity. Genetic ablation of C1qc substantially attenuated this BBB damaging effect, C1qc-deficient migrasomes exhibited protective properties. Our findings, for the first time, reveal the mechanistic role of C1qc and migrasomes in ICH pathogenesis and establish microglia-derived migrasomes as promising therapeutic targets, providing novel avenues to improve neurologic outcomes after ICH.

Keywords:  C1qc; blood‒brain barrier; intracerebral haemorrhage; microglia; migrasomes

DOI:  https://doi.org/10.1002/jev2.70377
Dev Cell. 2026 Oct 06. pii: S1534-5807(26)00353-9. [Epub ahead of print]

Inducible human yolk sac myeloid progenitors model myeloid ontogeny and enable tissue-resident macrophage replacement in vivo.

Anna Martinez-Muriana, Nicola Fattorelli, Leen Wolfs, Lena Jutz, Emanuela Pasciuto, Heidi Denton, Maxim van Hoek, Jessie Premereur, Gaia Zen, Baukje Bijnens, Alma Mohebiany, Tim Meese, Arthi Shanmugavadivu, V Hugh Perry, Bart De Strooper, Renzo Mancuso.

  Tissue-resident macrophages (TRMs) are involved in the surveillance and maintenance of tissue homeostasis, yet their dysfunction is a hallmark of human diseases. Although mouse TRMs arise from sequential migrations of yolk sac progenitors, limited access to human embryonic tissue has hindered the study of the origin of human TRMs. Here, we develop an in vitro system that generates inducible yolk sac myeloid progenitors (iYSMPs) to model human myeloid ontogeny. iYSMPs share the transcriptomic profile of yolk sac progenitors from human embryos and differentiate into macrophages, granulocytes, and erythroid lineages in vitro, mimicking human ontogeny. Upon systemic xenotransplantation, iYSMPs acquire organ-specific TRM identities and differentiate into microglia, border-associated macrophages, Kupffer cells, and cardiac and renal macrophages. These findings define a human yolk sac progenitor state with broad TRM differentiation potential, opening avenues for investigating human myeloid ontogeny and developing macrophage cell replacement therapies to treat human diseases.

Keywords:  cell replacement; human; microglia; myeloid cells; ontogeny; tissue-resident macrophages; yolk sac

DOI:  https://doi.org/10.1016/j.devcel.2026.09.005