bims-microg 2026-05-24 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–05–24
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Foamy microglia link oxylipins to disease progression in multiple sclerosis.
Spatial proteomic analysis in human Alzheimer's disease brains enables identification of microenvironment-dependent microglial cell states.
Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice.
Identification of secondary microglial formation centers in the human fetal brain.
A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions.
Parkinson's disease beyond the brain: erythrocyte α-synuclein transfer across the blood-brain barrier.
Hybrid dextran/fibronectin nanogels for brain-targeted mitophagy inducer delivery to alleviate neuroinflammation and neuronal loss of Parkinson's disease.
Vespakinin-M delineates an AMPK/mTOR-arginine-TCA cycle axis to act as an immunometabolic switch in post-stroke microglia.
Illuminating proinflammatory myeloid cells with PET tracers targeting GPR84.
A novel interoceptive subfornical organ to infralimbic cortex mechanism relays airway inflammation effects on fear extinction.
IL-1β-mediated interaction between Müller cells and microglia through CXCL1/5-CXCR2 aggravates visual dysfunction in experimental glaucoma.
The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models.
Plumbagin Ameliorates Multiple Sclerosis by Inducing DDX3X-Mediated Stress Granule Assembly in Mice.
Lactobacillus plantarum enhances cognition through acetate-modulated microglia function.
Astrocytes reduce microglial activation and enhance adult hippocampal neurogenesis in acute inflammation.
O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology.
Targeting MEF2A suppresses microglial hyperactivation and synaptic phagocytosis to attenuate epilepsy pathogenesis.
Myeloid Cell Protein Tyrosine Phosphatase 1B Drives Retinal Neurodegeneration in Diabetic Mice.
Mechanosensitive ion channel TRPV4 inhibition alleviates glaucomatous inflammation by regulating microglial ferroptosis.
Microglia maintain retinal redox homeostasis following ablation of rod photoreceptors in zebrafish.

Nat Neurosci. 2026 May 21.

Foamy microglia link oxylipins to disease progression in multiple sclerosis.

Netherlands Brain Bank

Multiple sclerosis (MS) is a chronic neuroinflammatory disease in which demyelinating white matter lesions accumulate and expand, driving irreversible disability. Here we identify a distinct population of foamy GPNMB+ microglia/macrophages associated with lesion expansion in secondary progressive MS. Using integrated lipidomic, transcriptomic, proteomic, chemical proteomic and histological analyses of human postmortem MS lesions, we show that lesions containing foamy microglia/macrophages exhibit disrupted lipid metabolism, lysosomal stress and markers associated with heightened phagocytosis and antigen presentation without classical pro-inflammatory signatures. These lesions are enriched for oxylipins, bismonoacylglycerolphosphates and cholesterol esters, and are associated with increased B cell infiltration and IgG1. Monoacylglycerol lipase (MAGL), a lipid-metabolizing enzyme enriched in lesions with foamy microglia/macrophages, emerged as a potential therapeutic target. Inhibition of MAGL promoted lesion recovery and reduced microgliosis in a mouse model of demyelination. Finally, oxylipins in cerebrospinal fluid correlate with the proportion of foamy lesions, suggesting potential biomarkers for progression. Our findings implicate disturbed lipid metabolism in chronic MS pathology and suggest that foamy microglia/macrophages are an interesting cell type to target for progressive disease.

DOI: https://doi.org/10.1038/s41593-026-02302-3
Nat Neurosci. 2026 May 18.

Spatial proteomic analysis in human Alzheimer's disease brains enables identification of microenvironment-dependent microglial cell states.

Paula Sanchez-Molina, Dennis-Dominik Rosmus, Dillon Brownell, Mert Meral, Cavanagh Gohlich, Aditya Pratapa, Yaser Peymanfar, Alyssa Whitley, Yue Hou, Nadezhda Nikulina, Alina Bogachuk, Ellen Lara Bouchard, Aude Chiot, Heidrun Kuhrt, Peter Wieghofer, Randall Woltjer, Fabian Svara, Oliver Braubach, Bahareh Ajami.

Disease-associated microglial states are thought to contribute to Alzheimer's disease (AD) progression, but characterizing them and their relationships to pathology remains challenging. Here we introduce CODEX-CNS-a multiplexed protein imaging technology with a custom data analysis pipeline for use in human brain samples. We profiled 704,706 cells in samples from the frontal cortex of 8 people with AD and 8 healthy controls and mapped features including blood-brain barrier, meningeal components and cell-cell interactions within the same tissue sections. Amongst the myeloid cell populations we identified, we found a border-associated macrophage-like microglial subset associated with aging. Further classifying myeloid cell subsets based on their spatial neighborhood, we identified a border-associated macrophage-like microglial subpopulation that was associated significantly with dense amyloid-β plaques, which we termed human plaque-associated microglia. This work offers insights into myeloid cell heterogeneity in AD and provides a new spatial approach to characterizing brain cells at the single-cell protein level.

DOI: https://doi.org/10.1038/s41593-026-02267-3
Mol Neurodegener. 2026 May 22.

Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice.

Ashish Sharma, Emiko Segawa, Xiaoying Chen, Sohui Park, Shoutang Wang, Riley E Irmen, Nicholas J Constantino, Chanung Wang, Michael F Kanan, Marco Colonna, Shannon L Macauley, Jocelyn Y Cheng, Ken Hatanaka, Margaret Moline, Erik S Musiek.

   BACKGROUND: Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer's disease (AD). The orexin/hypocretin system regulates sleep-wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.
METHODS: PSAPP mice received lemborexant (10 or 30 mg/kg/day), doxepin (35 mg/kg/day), or vehicle for 6 weeks beginning prior to plaque onset or 4 weeks after established pathology. Sleep was assessed by piezoelectric monitoring and EEG/EMG polysomnography. Amyloid pathology and microglial responses were quantified by immunohistochemistry, confocal microscopy, and single-cell RNA sequencing. Microglial depletion was induced with the CSF1R inhibitor PLX3397.
RESULTS: Lemborexant enhanced sleep quality with less active-phase sedation than doxepin. Both drugs reduced initial diffuse plaque deposition, but only lemborexant prevented fibrillar plaque accumulation in young mice and slowed plaque growth in older mice. Lemborexant increased peri-plaque microglial CD68 expression and enhanced Aβ phagocytosis in vivo. Single-cell transcriptomics revealed a shift toward activated, DAM-like microglial states with upregulation of phagocytic genes without broad inflammatory induction. Microglial depletion abolished lemborexant's anti-amyloid effects.
CONCLUSIONS: Lemborexant mitigates amyloid pathology by augmenting microglial phagocytic function, positioning DORAs as promising therapeutics that couple sleep promotion with beneficial microglial modulation.

Keywords:  Alzheimer’s disease; Amyloid plaques; Microglia; Orexin; Sleep

DOI:  https://doi.org/10.1186/s13024-026-00948-y
J Exp Med. 2026 Jun 01. pii: e20251801. [Epub ahead of print]223(6):

Identification of secondary microglial formation centers in the human fetal brain.

Chenyun Song, Xinyu Chen, Rong Ji, Yang Liu, Yawen Han, Fangzhou Ye, Ling Zhang, Li Li, Lu Gao, Qizhi He, Lixiang Ma, Hexige Saiyin.

Microglia migrate from the yolk sac and populate the developing brain. How microglia expand rapidly to meet the microglial demand in fast-expanding human fetal brains remains uncharted. Using thick sections in 5-22-gestational week (gw) brains and super-resolution scanning, we identified a large proliferative microglial aggregate (2.129 mm2) near the lateral ganglionic eminence (>12.5 gw), expanding in Down's syndrome (DS) (4.767 mm2) and Edwards syndrome (ES) (3.437 mm2) fetal brains. Ki67+ microglia within the aggregates accounted for 26.65% (DS: 38.9%; ES: 46.3%) compared with 6.32% (DS: 6.01%; ES: 5.2%) in scattered microglia. This aggregate region contained a distinct microglial population characterized by the absence of phagocytic structures and complex processes, high CSF-1R expression, abundant IL-34+ cells, and some SPP1+ bipolar microglia. We termed this structure the secondary microglial formation center (SMFC). Chimeric microglia-human cortical organoids recapitulated the SMFC in an IL-34- and CSF-1R-dependent manner, indicating that the human SMFC may compensate for the microglial shortage during the fastest expansion period.

DOI: https://doi.org/10.1084/jem.20251801
Nat Commun. 2026 05 18. pii: 3858. [Epub ahead of print]17(1):

A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions.

Erin L Aboelnour, Veronica R Vanoverbeke, Elizabeth A Maupin, Madelyn M Hatfield, Katrina L Adams.

Demyelinating diseases, including multiple sclerosis (MS), are characterized by loss of myelin and progressive neurodegeneration. It remains unclear if demyelination mouse models, such as cuprizone (CPZ) and lysophosphatidylcholine (LPC) elicit distinct responses or are comparable to human disease. Here, we integrate new and published single-cell transcriptomic datasets from CPZ- and LPC-induced demyelination and compare them with human MS data. We find that CPZ induces a distinct, stressed oligodendrocyte (OL) state, marked by Cdkn1a and Nupr1, that resembles phenotypes in MS lesions. The models converge on an immune responsive OL state expressing Socs3, B2m, and interferon-response genes during remyelination. Mouse microglia share a conserved activation program, although LPC drives a stronger, prolonged response. However, neither model captures the oligodendrocyte progenitor and microglial heterogeneity observed in MS. These results provide a cross-model, cross-species atlas of glial states and offer a framework to strategically leverage mouse models to study myelin injury and repair.

DOI: https://doi.org/10.1038/s41467-026-72383-y
Brain. 2026 May 19. pii: awag179. [Epub ahead of print]

Parkinson's disease beyond the brain: erythrocyte α-synuclein transfer across the blood-brain barrier.

Ying Yang, Qi Liu, Tao Zhou, Jun Chen, Wenjing Li, Wentao Chen, Shaopeng Zeng, Huan Liu, Pan Wang, Peizheng Yang, Bin Xu, Shiping Liu, Xiao Xiong, Bingbing Cheng, Jing Zhang.

  Parkinson's disease is characterized by the accumulation and propagation of α-synuclein pathology in the central nervous system, yet the contribution of peripheral α-synuclein sources remains unclear. Here, we identify erythrocytes as an important reservoir of α-synuclein and demonstrate that bone marrow-derived erythrocytic α-synuclein likely contributes to brain pathology and Parkinson's disease-related neurodegeneration. Using human tissues and mouse models, we show that erythrocytes harbour abundant α-synuclein species. Bone marrow transplantation revealed widespread distribution of bone marrow-derived α-synuclein in peripheral organs, with detectable but substantially lower levels in the brain. Within the central nervous system, bone marrow-derived α-synuclein preferentially accumulated in resident microglia, as confirmed by immunophenotyping and single-nucleus RNA sequencing, and was associated with microglial activation. Furthermore, erythrocyte-derived extracellular vesicles carrying α-synuclein can be readily taken up by microglia in vivo. Functionally, elevated levels of bone marrow-derived α-synuclein in the mouse brain resulted in dopaminergic dysfunction with a mild neurodegenerative phenotype under baseline conditions. Importantly, blood-brain barrier integrity critically regulated peripheral α-synuclein entry into the central nervous system. Disruption of the blood-brain barrier by endotoxin administration, mannitol treatment or focused ultrasound markedly increased the entry of peripheral α-synuclein into the brain, aggravating neurodegeneration and behavioural deficits. Collectively, these findings identify bone marrow-derived erythrocytic α-synuclein as a systemic contributor to the pathogenesis of Parkinson's disease and highlight blood-brain barrier integrity as a key permissive regulator of peripheral-to-central α-synuclein transmission.

Keywords:  Parkinson’s disease; blood–brain barrier; bone marrow; red blood cells; synucleinopathies; α-synuclein

DOI:  https://doi.org/10.1093/brain/awag179
Carbohydr Polym. 2026 Aug 01. pii: S0144-8617(26)00527-8. [Epub ahead of print]385 125410

Hybrid dextran/fibronectin nanogels for brain-targeted mitophagy inducer delivery to alleviate neuroinflammation and neuronal loss of Parkinson's disease.

Meng Qin, Huxiao Sun, You Ji, Zhuo Li, Cheng Ni, Zhiqiang Wang, Dina Maciel, João Rodrigues, Xiangyang Shi, Mingwu Shen.

  Parkinson's disease (PD) is characterized by progressive dopaminergic neuron loss, chronic neuroinflammation, and α-synuclein aggregation. Blood-brain barrier (BBB)-penetrable, dual-target nanomedicines for microglial inflammation and neuronal degeneration remain challenging. In this study, we fabricated a brain-targeted, pH- and reactive oxygen species (ROS)-responsive nanogel (NG) platform using dextran (Dex) as the main polysaccharide backbone, crosslinked with inflammation-targeting fibronectin (FN), and loaded with neuroprotective quercetin (Que). Dex-FN/Que NGs exhibited a uniform spherical morphology with an average diameter of 187 nm, favorable colloidal stability, and stimuli-triggered drug release behavior. Abundant hydroxyl groups on Dex enabled efficient BBB penetration, while FN mediated integrin-dependent internalization in microglia and neurons. These NGs suppressed the nuclear factor-kappa B (NF-κB) signaling pathway, scavenged ROS, promoted favorable microglial polarization, and balanced oxidative stress. Meanwhile, mitophagy flux activated by the NGs in neurons exerted strong neuroprotection effect. In a mouse model of PD, Dex-FN/Que NGs effectively crossed the BBB and accumulated in injured brain regions, significantly protecting dopaminergic neurons, improving motor function, and relieving depressive-like behaviors. Therapeutic benefits arose from normalized microglial polarization, reduced oxidative stress, and inhibited neuronal ferroptosis. This Dex-based stimuli-responsive nanoplatform provides a promising brain-targeted strategy for the treatment of PD and other neurological disorders.

Keywords:  Blood-brain barrier; Fibronectin; Nanogels; Parkinson's disease; Responsive drug release

DOI:  https://doi.org/10.1016/j.carbpol.2026.125410
Redox Biol. 2026 May 12. pii: S2213-2317(26)00208-9. [Epub ahead of print]94 104210

Vespakinin-M delineates an AMPK/mTOR-arginine-TCA cycle axis to act as an immunometabolic switch in post-stroke microglia.

Dexiao Wang, Jingyu Zhang, Zhejun Zhuang, Qian Wang, Jie Li, Xue Wang, Kunkun Li, Yunyun Liu, Yanhui Cao, Lijuan Li, Yunwu Zhang, Yu Zhao, Yingjun Zhao, Hairong Zhao, Chenggui Zhang.

  Despite advances in recanalization therapy for ischemic stroke, effective neuroprotection against cerebral ischemia-reperfusion injury (CIRI) remains an unmet need, largely due to persistent microglia-driven neuroinflammation and associated oxidative stress. Vespakinin-M (VK) is a naturally neuroprotective peptide isolated from wasp venom that can cross the blood-brain barrier. Although VK has been shown to improve functional outcomes in preliminary stroke models, its underlying mechanisms remain unclear. Here, we show that administration of VK alleviates neuroinflammation and oxidative damage in a mouse stroke model. This neuroprotection is orchestrated by microglial metabolic reprogramming, which shifts their energy metabolism from aerobic glycolysis toward oxidative phosphorylation (OXPHOS) and their functional phenotype from pro-inflammatory M1 to reparative M2. Integrated multi-omics and isotopic tracing uncover that VK redirects arginine metabolism to generate fumarate. This directly couples amino acid catabolism with the tricarboxylic acid (TCA) cycle, thereby restoring mitochondrial bioenergetics and redox balance. Mechanistically, VK activates the energy sensor AMPK while inhibiting the anabolic regulator mTOR. AMPK knockdown partially abolishes the beneficial effects of VK, establishing the AMPK/mTOR axis as the upstream regulator of this arginine-centric metabolic rewiring. Interestingly, VK retains the ability to stimulate de novo arginine synthesis even under arginine-deprived conditions, and its efficacy is synergistically enhanced with arginine supplementation. Together, these findings define an immunometabolic axis-AMPK/mTOR-arginine-TCA cycle coupling-that dictates microglial fate after stroke, and suggests VK as a therapeutic agent capable of concurrently targeting neuroinflammation, mitochondrial dysfunction, and metabolic imbalance.

Keywords:  Arginine metabolism; Immunometabolism; Ischemic stroke; Microglia; Mitochondrial dysfunction; Vespakinin-M

DOI:  https://doi.org/10.1016/j.redox.2026.104210
Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2536372123

Illuminating proinflammatory myeloid cells with PET tracers targeting GPR84.

Mausam Kalita, Renesmee C Kuo, Valentina Straniero, Samantha T Reyes, Mallesh Pandrala, Alessia Lanzini, Sara Marsango, Desiree D'Moore, Piper Mahn, Andrew Setiadi, Mira Sundar, Spencer Mak, Sydney Nagy, Israt S Alam, Poorva Jain, Grace Inay, Rim Malek, Allen F Brooks, Corinne Beinat, Ermanno Valoti, Peter J H Scott, Graeme Milligan, Michelle L James.

  Innate immunity mediated by myeloid cells defends against infection and injury, but when chronically activated, it drives tissue damage and neurodegeneration. Molecular imaging with positron emission tomography (PET) enables noninvasive, real-time monitoring of such processes in vivo. However, most current neuroinflammation PET tracers lack specificity for activated myeloid cells. G protein-coupled receptor 84 (GPR84) is a promising biomarker that is selectively upregulated on activated microglia and macrophages. Here, we report the development and validation of two fluorine-18-labeled GPR84 tracers, [18F]MGX-110S and [18F]MGX-111S. Both exhibit specific binding to human GPR84-expressing cells, with [18F]MGX-110S demonstrating superior affinity, selectivity, and signal-to-background ratio. [18F]MGX-110S enables sensitive detection of systemic- and neuro-inflammation in LPS-treated mice and outperforms PET images obtained using a radiotracer specific for translocator protein 18 kDa in 5xFAD mice-revealing pathology-correlated activation across cortical, hippocampal, and thalamic regions. Taken together, our data indicate that [18F]MGX-110S is a highly sensitive and specific tool for visualizing maladaptive myeloid cell activation; its clinical translation could enable more precise detection and staging of inflammation in addition to improved therapeutic monitoring in neurodegenerative disorders and more broadly in inflammatory diseases.

Keywords:  Alzheimer’s disease; G protein–coupled receptor 84 (GPR84); innate immune activation; neuroinflammation; positron emission tomography (PET)

DOI:  https://doi.org/10.1073/pnas.2536372123
J Neuroinflammation. 2026 May 18.

A novel interoceptive subfornical organ to infralimbic cortex mechanism relays airway inflammation effects on fear extinction.

Emily Allgire, Jaclyn W McAlees, Rebecca A Ahlbrand, Elizabeth Mancz, Lauren L Vollmer, Andrew Winter, Katherine M J McMurray, Laura Maile, Bryan Sanders, William G Ryan, Allan-Hermann Pool, Igal Ifergan, Eric S Wohleb, Steve Davidson, Robert E McCullumsmith, Ian P Lewkowich, Renu Sah.

  There is growing interest in the impact of internal body states on the brain and behavior. The detrimental effects of chronic lung inflammation on mental health are well recognized; however, underlying mechanisms are not known. Here, using a murine model of allergic asthma we report compromised fear extinction in mice with severe but not mild airway inflammation (AI); an effect abolished by anti-interleukin-17 A (IL-17 A) antibodies. Investigation of innate immune cells, microglia as-well-as transcriptomic signatures in the subfornical organ (SFO), a brain interoceptive node lacking a traditional blood-brain-barrier, revealed significant alterations in severe AI mice. IL-17 Receptor A (IL-17RA) was expressed in SFO microglia and upregulated in severe AI mice. Notably, ablation of microglial IL-17RA improved fear extinction in severe AI mice. Furthermore, we identified direct SFO projections to the infralimbic (IL) cortex, a key area regulating extinction. Importantly, chemogenetic inhibition of the SFO-IL circuit led to improved fear extinction in severe AI mice. Collectively, we report a unique body-to-brain interoceptive mechanism engaging the SFO microglia and an SFO-to-IL circuit, through which airway inflammatory mediators compromise fear extinction. Beyond asthma, our findings are relevant to other pulmonary pathologies (e.g. bacterial pneumonia, ARDS, COVID-19) highlighting a risk for cortical dysfunction and fear pathologies such as PTSD.

Keywords:  Airway inflammation; Fear; Infralimbic cortex; Interleukin 17A; Microglia; Subfornical organ

DOI:  https://doi.org/10.1186/s12974-026-03834-y
J Neuroinflammation. 2026 May 21.

IL-1β-mediated interaction between Müller cells and microglia through CXCL1/5-CXCR2 aggravates visual dysfunction in experimental glaucoma.

Xiaoyu Xin, Luying Han, Yuntao Qu, Lujia Zhang, Xiaoli Zhang, Jiarui Li, Bo Lei, Yong-Chen Wang, Zhongfeng Wang.

PURPOSE: Glaucoma is an optic neuropathy characterized by progressive death of retinal ganglion cells (RGCs), ultimately leading to blindness. Increasing evidence demonstrates that interactions among retinal glial cells exacerbate retinal inflammatory responses, which is closely associated with RGC injury. However, the detailed mechanisms governing these glial cell interactions remain largely unknown. This study aims to investigate the possible roles and the potential mechanisms of interleukin-1β (IL-1β) in mediating the interaction between Müller cells and microglia in glaucoma.
METHODS: The experimental glaucoma model of chronic ocular hypertension (COH) was established in adult male mice by injection of micro-magnetic beads into the anterior chamber. Western blotting, quantitative real-time polymerase chain reaction, immunofluorescence, transwell co-culture of glial cells, RNA sequence, swept-source optical coherence tomography-based imaging and flash visually evoked potentials were employed to investigate the underlying mechanisms about the interaction of Müller cells and microglia in retina after IL-1β stimulation, along with their impact on visual functions.
RESULTS: We showed that in COH retinas, IL-1β activated Müller cells and microglia, and promoted the recruitment of microglia to the ganglion cell layer. Mechanistic studies revealed that activated Müller cells released C-X-C motif chemokine ligand 1/5 (CXCL1/5) through the NF-κB and p38 MAPK signaling pathways. These chemokines bond to CXC chemokine receptor 2 (CXCR2), inducing microglial activation and migration. This activation led to a significant increase in the expression of pro-inflammatory factors, which contributed to RGC death and subsequent visual function decline. Importantly, inhibition of the CXCL1/5-CXCR2 axis substantially reversed RGC loss and improved visual function.
CONCLUSIONS: IL-1β plays a positive feedback role in glial cell interactions, amplifying retinal inflammatory responses and impairing visual function. These findings demonstrate that inhibiting the interaction between Müller cells and microglia effectively protects RGCs, offering a promising strategic approach for glaucoma prevention and treatment.

DOI: https://doi.org/10.1186/s12974-026-03884-2
J Neuroinflammation. 2026 May 20.

The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models.

Hyun-Ju Lee, Jaewoo Seok, Sora Kang, Seokjun Oh, Jeong-Woo Hwang, Yu-Jin Kim, Jinsoo Seo, Hyang-Sook Hoe.

   BACKGROUND: BMS-754807 is a dual inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) that is in phase II clinical trials for the treatment of HR-positive and HER2-negative breast cancer. Because IGF-1R signaling regulates inflammatory responses, pharmacological modulation of IGF-1R may have therapeutic potential for Alzheimer's disease (AD); however, the effects of BMS-754807 on neuroinflammatory responses/AD pathology and cognitive function have not been fully investigated.
METHODS: We examined whether BMS-754807 modulates neuroinflammation and AD pathologies in multiple in vivo animal models and in vitro human models. BMS-754807 (20 mg/kg, i.p.) was systemically administered in wild-type mice challenged with LPS, 5xFAD mice, and PS19 transgenic mice. In addition, human-induced pluripotent stem cell (hiPSC)-derived microglia challenged with LPS and AD hiPSC-derived neurons were treated with 2.5 µM BMS-754807. For all models, the effects of BMS-754807 treatment were analyzed by real-time PCR, immunofluorescence staining, western blotting, ELISA, and/or activity assays.
RESULTS: BMS-754807 treatment significantly decreased p-IGF-IR (on-target) levels, LPS-induced proinflammatory cytokine production, and reactive oxygen species levels; restored HO-1 expressions; and inhibited AKT/STAT3 signaling in BV2 microglial cells. Similarly, BMS-754807 treatment reduced LPS-evoked proinflammatory cytokine expressions in primary microglial cells and primary astrocytes. In addition, BMS-754807 administration mitigated LPS-stimulated gliosis, microglial/astrocyte-associated dynamics, STAT3/NF-κB phosphorylation, and potentially NLRP3 inflammasome in vitro and/or in WT mice. Moreover, BMS-754807 treatment suppressed LPS-mediated proinflammatory responses through IGF-1R and NLRP3 in BV2 microglial cells. In 5xFAD mice, BMS-754807 administration downregulated IGF-1R phosphorylation, microgliosis/astrogliosis-related dynamics, and AKT/P38/STAT3 pathway. Notably, BMS-754807 treatment also diminished LPS-induced proinflammatory cytokine levels and STAT3/NF-κB signaling in human microglial models. Furthermore, BMS-754807 treatment decreased Aβ40/Aβ42 levels in hiPSC-derived AD neurons, and increased short-term spatial memory and reduced Aβ plaque accumulation by decreasing β-secretase (BACE1) activity in 5xFAD mice. Finally, in hiPSC-derived AD neurons and PS19 mice, BMS-754807 treatment significantly attenuated tau hyperphosphorylation, CaMKIIα phosphorylation, and tau-mediated astroglial activation.
CONCLUSIONS: Taken together, our results suggest that BMS-754807 exerts anti-inflammatory and potential disease-modifying effects by attenuating LPS/Aβ/tau-evoked glial activation and reducing Aβ and tau pathologies in both human cellular and mouse models of neuroinflammation and AD. Furthermore, BMS-754807 administration improved specific domains of cognitive function in vivo. These findings support pharmacological inhibition of IGF-1R as a potential therapeutic approach for neuroinflammation-associated diseases including AD.

Keywords:  Aβ pathology; BMS-754807; IGF-1R/IR inhibitor; Neuroinflammation; Tauopathy

DOI:  https://doi.org/10.1186/s12974-026-03855-7
Pharmacol Res. 2026 May 20. pii: S1043-6618(26)00172-6. [Epub ahead of print] 108257

Plumbagin Ameliorates Multiple Sclerosis by Inducing DDX3X-Mediated Stress Granule Assembly in Mice.

Minglv Fang, Ying Liu, Yongli Han, Yashi Xu, Jing Yu, Yingxuan Yan, Zhigang Jin, Xiaojun Wu, Cheng Huang, Shengjie Fan.

  Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with limited therapeutic options. Stress granules (SGs), membraneless organelles formed via liquid-liquid phase separation (LLPS) in response to cellular stress, function as a cytoprotective mechanism against stress induced apoptosis and pyroptosis. SGs can counteract NLRP3 inflammasome by sequestering dead-box helicase 3 X-linked (DDX3X), thereby promoting the survival of pyroptotic cells. Here, we identified that plumbagin (PL), a natural naphthoquinone with antioxidant and anti-inflammatory properties, as a novel SG inducer. In microglia, PL induced SGs that suppressed NLRP3-mediated pyroptosis and subsequent mitochondrial dysfunction, with DDX3X as a potential target. Furthermore, PL alleviated neuroinflammation and demyelination and suppressed oxidative stress in the CNS of both the cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) mouse models. Our findings reveal that PL can mitigate neuroinflammation and myelin damage by modulating the DDX3X-SG axis, supporting a novel therapeutic strategy for MS.

Keywords:  DDX3X; Multiple sclerosis; NLRP3 inflammasome; Plumbagin; pyroptosis; stress granules

DOI:  https://doi.org/10.1016/j.phrs.2026.108257
Brain Behav Immun. 2026 May 19. pii: S0889-1591(26)00569-6. [Epub ahead of print]137 106821

Lactobacillus plantarum enhances cognition through acetate-modulated microglia function.

Tingyi Zhou, Yi Yue, Juncai Leng, Yiming Jiang, Han Liu, Shiqi Zhang, Zhengchao Yang, Wei Zhao, Li Li.

  Gut microbiota profoundly influences cognition through immune and metabolic pathways, but how specific strains contribute to these processes remain unclear. Here, we show that supplementation with Lactobacillus plantarum C067 enhanced spatial and fear-associated memory, while restoring hippocampal cytokine expression and microglial morphology in both healthy and antibiotic-treated mice. L. plantarum also reshaped microbial composition and elevated short-chain fatty acids, particularly acetate. Acetate supplementation replicated the cognitive benefits and restored microglial homeostasis. Mechanistically, acetate exerted anti-inflammatory effects via acetyl-CoA synthetase 2 (ACSS2)-dependent acetyl-CoA production in microglia, reducing mitochondrial oxidative stress and cytokine release. Together, these findings identify an ACSS2-mediated microbe-metabolite-microglia axis that underlies the cognitive benefits of L. plantarum, providing a mechanistic framework for probiotic- and metabolite-based interventions against cognitive decline.

Keywords:  Cognitive enhancement; Gut-brain axis; Lactobacillus plantarum; Microglia; Short-chain fatty acids

DOI:  https://doi.org/10.1016/j.bbi.2026.106821
Brain Behav Immun. 2026 May 19. pii: S0889-1591(26)00562-3. [Epub ahead of print] 106814

Astrocytes reduce microglial activation and enhance adult hippocampal neurogenesis in acute inflammation.

Marta Vilademunt, Irmak Çabas, Fabio Grieco, Charline Carron, Thibault Sprenger, Thomas Larrieu, Jean-René Cardinaux, Nicolas Toni.

  Adult hippocampal neurogenesis is a major process of neuronal plasticity involved in mood regulation and memory and is tightly regulated by the neurogenic niche that relays signaling from the periphery. Neuroinflammation is principally mediated by microglia and strongly impairs adult neurogenesis, but the contribution of astrocytes to this effect is unclear. In this study, we used in vitro and in vivo approaches to investigate the role of astrocytes in the microglial inflammatory response and its impact on adult hippocampal neurogenesis. In vitro, we found that astrocytes attenuated the response of microglia to Lipopolysaccharide (LPS) inflammatory stimulation, through both secreted factors and direct membrane-bound interactions, with secreted factors displaying the strongest effect. Furthermore, astrocytes rescued the inhibition of adult hippocampal stem cell proliferation by LPS-stimulated microglia. In vivo, the administration of astrocyte-conditioned solution (ACS), containing the astrocyte secretome, attenuated LPS-induced sickness and depressive-like behavior, microglial and astrocytic reactivity in the dentate gyrus and restored the number of neural intermediate progenitors. Together, these findings indicate that astrocytes modulate microglia response to inflammatory cues and highlight the astrocytic secretome as a potent anti-inflammatory and pro-neurogenic agent, with potential implications for neuroinflammation-associated conditions such as Alzheimer's disease and mood disorders.

Keywords:  Astrocytes; Depressive-like behavior; Inflammation; Microglia; Microglia activation; Neurogenesis; Neurogenic niche; Sickness behavior

DOI:  https://doi.org/10.1016/j.bbi.2026.106814
Cell Death Dis. 2026 May 21.

O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology.

Dong Yeol Kim, Sang-Min Kim, Chanhaeng Lee, Inn-Oc Han.

Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial polarization, elevated NF-κB signaling, and NLRP3 inflammasome activation. In an LPS-induced neuroinflammation model exhibiting AD-relevant inflammatory and cognitive features, as well as in in vitro microglial cultures, LPS exposure led to a pronounced decrease in O-GlcNAcylation, particularly within Iba1-positive microglia. Systemic or in vitro treatment with glucosamine (GlcN) effectively restored O-GlcNAc levels, suppressed M1-associated inflammatory pathways, and promoted an anti-inflammatory M2 phenotype. Mechanistically, GlcN enhanced O-GlcNAcylation of NF-κB subunits p65 and c-Rel, limiting their nuclear translocation and downstream pro-inflammatory gene expression. Notably, GlcN treatment ameliorated LPS-induced memory deficits and neuronal loss in mice. Collectively, these findings suggest that O-GlcNAcylation acts as a modulatory regulator of microglial activation and neuroinflammation in AD, and that enhancing O-GlcNAcylation may represent a potential therapeutic strategy to preserve immune homeostasis and neuronal integrity.

DOI: https://doi.org/10.1038/s41419-026-08862-3
Cell Death Dis. 2026 May 22.

Targeting MEF2A suppresses microglial hyperactivation and synaptic phagocytosis to attenuate epilepsy pathogenesis.

Jingheng Wu, Jiayuanyuan Fu, Shuai Wang, Yuzhang Wu, Xu Wang, Shangang Feng, Qi Shi, Yuhao Wang, Yetong Shi, Yehong Fang, Yu Lan, Qiaoli Wu, Chuan Du, Shaoya Yin, Lixia Xu, Hua Yan.

Microglia's role in epilepsy through neuroimmune communication is poorly understood. Mechanisms by which neurons activate microglia and how microglia affect neuronal activity to drive seizure-related inflammation remain unclear. Here, we elucidated a crucial axis connecting pathological adenosine triphosphate (ATP) release induced by epileptiform neuronal activity to microglial MEF2A-dependent hyperactivation, which exacerbates epilepsy pathology. In epilepsy models, seizures cause excessive ATP release, activating microglial P2X7 receptors, causing CAMKII phosphorylation. This triggers HDAC5 translocation, freeing MEF2A for acetylation, and enhancing transcription. Acetylated MEF2A increases CD74 and NEK7 expressions, enhancing NLRP3 inflammasome activation and microglial hyperactivation, worsening neuronal hyperexcitability by increasing inhibitory synapses clearance. Targeting microglial MEF2A with parecoxib or AAV knockdown reduced seizure severity and cognitive deficits and maintained synaptic inhibition by reducing excessive microglial phagocytosis. This reveals an ATP-P2X7-Ca2⁺- MEF2A signaling axis connecting neuronal injury with pathogenic microglial activation, suggesting MEF2A as a therapeutic target for microglial-neuronal homeostasis restoration in epilepsy pathology.

DOI: https://doi.org/10.1038/s41419-026-08860-5
Diabetes. 2026 May 21. pii: db250904. [Epub ahead of print]

Myeloid Cell Protein Tyrosine Phosphatase 1B Drives Retinal Neurodegeneration in Diabetic Mice.

Ayaz Ali, Morgan Boyne, Abrar Othman, Sarah Kamli-Salino, Lucia Kuffova, John V Forrester, Mirela Delibegovic.

Diabetic retinopathy (DR) is the leading cause of vision loss in the working-age population, with public health economic implications worldwide. Systemic inflammation and leukocyte activation are early events in diabetes, whereas microglial activation, neuroinflammation, and retinal neurodegeneration are early events in DR. Protein tyrosine phosphatase 1B (PTP1B) plays a complex role in monocyte and macrophage activation, which may affect DR. We investigated the role of myeloid cell-specific PTP1B using LysMcre-PTP1B fl/fl (LysM-PTP1B) transgenic mice, as well as pharmacological inhibition with a PTP1B inhibitor, MSI-1436, in the early stages of DR. Mice were rendered diabetic for 6 weeks using anomer-equilibrated streptozotocin (STZ). Retinal changes were evaluated by histology and immunohistochemistry, and systemic leukocyte activation by flow cytometry. Mitochondrial function in high-glucose-concentration-challenged, cultured bone marrow-derived macrophages (BMDMs) from LysM-PTP1B- and MSI-I436-treated mice was determined in vitro. Both myeloid cell-specific depletion and pharmacological inhibition of PTP1B prevented STZ-induced retinal neurodegeneration, development of acellular retinal capillaries, as well as microglial and systemic leukocyte activation without altering the development of diabetes. In vitro, inhibition of PTP1B prevented high-glucose-level-induced mitochondrial dysfunction in BMDMs. We conclude that inhibition of PTP1B prevents DR by decreasing myeloid cell-driven inflammation, and PTP1B represents a therapeutic target for prevention DR.
ARTICLE HIGHLIGHTS: Myeloid cell PTP1B is required to induce retinal neurodegeneration in diabetes. Both local (microglia) and systemic (bone marrow-derived) myeloid cells are implicated. Inhibition of myeloid cell PTP1B prevents development of acellular retinal capillaries in diabetic mice. PTP1B mediates superoxide production, decreases mitochondrial membrane potential, and, in female mice, increases macrophage cell death in chronic conditions associated with abnormally high glucose levels. Protective effects of PTP1B deletion on diabetic retinopathy were also observed in mice treated with the small molecular PTP1B inhibitor MSI-1436; both retinal neurodegeneration and local glial cell activation were decreased.

DOI: https://doi.org/10.2337/db25-0904
Int Immunopharmacol. 2026 May 20. pii: S1567-5769(26)00709-5. [Epub ahead of print]183 116863

Mechanosensitive ion channel TRPV4 inhibition alleviates glaucomatous inflammation by regulating microglial ferroptosis.

Xiaotong Zhang, Ying Su, Feng Wang.

  Glaucoma is a neurodegenerative disease characterized by the progressive and irreversible loss of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is a key factor in initiating pathological processes in acute glaucoma. This study aims to investigate the role of TRPV4 in mediating retinal inflammatory damage following acute glaucomatous injury. Using an in vitro elevated hydrostatic pressure (EHP) model established in BV2 microglia and an in vivo acute ocular hypertension (AOH) model in mice, we assessed microglial migration and polarization (M1/M2), lipid peroxidation, mitochondrial morphology, ferroptosis-related protein expression, and retinal ganglion cell survival. The function of TRPV4 was validated using the specific inhibitor HC-067047 and TRPV4 gene knockdown, and the p53/SLC7A11/GPX4 ferroptosis axis was investigated using the ferroptosis inhibitor Ferrostatin-1 (Fer-1), the p53 agonist Nutlin-3, and p53 gene knockdown. Results demonstrated that injury upregulates and activates TRPV4, inducing calcium influx in microglia. TRPV4 activation triggered ferroptosis by upregulating p53 and downregulating SLC7A11 and GPX4, thereby promoting pro-inflammatory M1 microglial polarization and exacerbating ganglion cell injury. Notably, pharmacological inhibition of TRPV4 reversed these responses, shifting microglia toward an anti-inflammatory M2 phenotype and mitigating ganglion cell loss. These findings demonstrate that TRPV4 activation drives ferroptosis via the p53/SLC7A11/GPX4 axis, thereby promoting microglial-mediated neuroinflammation, providing a new theoretical perspective for understanding the pathogenesis of neuroinflamation in glaucoma.

Keywords:  Acute glaucoma; Ferroptosis; Mechanosensitive ion channels; Microglia M1/M2 polarization; TRPV4

DOI:  https://doi.org/10.1016/j.intimp.2026.116863
J Biol Chem. 2026 May 18. pii: S0021-9258(26)02041-7. [Epub ahead of print] 113169

Microglia maintain retinal redox homeostasis following ablation of rod photoreceptors in zebrafish.

Michael Morales, Diana M Mitchell.

  Microglia rapidly respond to injury, stress, and perturbations to neurons in the brain and retina and perform phagocytosis to clear dying cells and debris. Oxidative stress is a feature of neurodegeneration, and while glia are crucial for managing such stress, microglia may also be dysfunctional in diseased tissue. Here we examine the role of microglia in management of oxidative stress and restoring redox homeostasis following death of rod photoreceptors in the larval zebrafish retina. Using rho:nfsb-eGFP transgenic zebrafish and treatment with the pro-drug metronidazole (MTZ), we coupled the generation of reactive oxygen species (ROS) in dying rods to their ablation. Microglia efficiently engulfed and cleared the ROS-laden rods, effectively undertaking the oxidative load. Despite abundant ROS upon MTZ-mediated cell death, oxidative stress overall was minimal in retinal tissue when microglia were present, indicating that they rapidly and efficiently performed redox functions. In irf8-/- mutants, which are deficient in microglia, retinas with MTZ-induced rod ablation showed widespread ROS that localized, at least in part, to Müller glia. Microglia deficient retinas showed evidence of increased oxidative stress, and increased numbers of "off-target" inner retinal neurons that stained positive for the cell death marker TUNEL. Supplementation with the antioxidant Glutathione modestly reduced the number of off-target TUNEL+ cells detected in microglia-deficient retinas following rod ablation. We also found that microglia may be important for mitigating effects of MTZ alone in the absence of Nfsb enzyme. Our results suggest that microglial redox functions are important in maintaining and restoring homeostasis following acute retinal damage.

Keywords:  Microglia; Müller glia; cell death; oxidative stress; photoreceptors; redox balance; retina

DOI:  https://doi.org/10.1016/j.jbc.2026.113169