bims-microg 2026-06-28 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–06–28
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4-Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR-Linked Pro-Clearance State.
Biomimetic Hydrogel System Targeting S100A8 Centered Neuroimmune Crosstalk and Hypoxia Induced Neuronal Injury.
Donor-specific pathological features associate with genetic background, lesion type distribution, and clinical heterogeneity in multiple sclerosis.
Targeting microglial circMBNL1 unlocks a novel nanomedicine therapeutic strategy for major depressive disorder.
Activation of microglial PPARγ by asperosaponin VI alleviates stress-induced depression and synaptic impairment.
Multi-dimensional decoding of the TSPO signal in animal models of neuroinflammation using fluorescence-conjugated DPA714.
Immune checkpoint LAG-3 governs stage-dependent and disease-associated microglial modules in ALS model mice.
PIM1-induced Drp1 phosphorylation disrupts microglial mitophagy and aggravates neuroinflammation.
Ventral striatal neuroimmune signalling biases the expression of social memory in male mice.
Astrocytic SCAP deletion ameliorates diabetes-associated cognitive impairment by suppressing microglial neuroinflammation and lipid droplet accumulation via the LCN2-24p3R-mTOR axis.
Divergent toxicity mechanisms of amyloid-beta aggregates arising from a single aggregation reaction.
Bone marrow mesenchymal stem cell-derived TSG-6 regulates microglial pyroptosis and alleviates bone cancer pain by inhibiting the NLRP3 inflammasome.
Gnao1 acts as a gatekeeper to alleviate neuropathic pain by silencing pro-nociceptive signaling cascades.
Oxymatrine alleviates cerebral ischemia-reperfusion injury by inhibiting microglia ferroptosis via NRF2 pathway activation.
Microglial SWELL1 deficiency drives male-specific seizure vulnerability but paradoxical neuroprotection through impaired phagocytosis.
GPNMB regulates EGFR mitochondrial translocation via HK2, influencing microglial respiratory chain and metabolic defects to promote polarization and stroke progression.
Integrative transcriptomic analysis identifies meningeal-hippocampal immune communication in Alzheimer's disease.
Inhibition of HSPA8 alleviates experimental autoimmune encephalomyelitis via dual modulation of NLRP3 inflammasome activation: suppressing both NF-κB-mediated priming and ASC-dependent assembly.
Time-resolved single-nucleus profiling of inter- and intracellular signaling in optic nerve injury: From the hyperacute phase to the acute phase.

Nat Neurosci. 2026 Jun 26.

The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.

Maria Jose Perez J, Alicia Lam, Christin Weissleder, Federico Bertoli, Hariam Raji, Mariella Bosch, Ivan Nemazanyy, Stefanie Kalb, Mohammed Kehili, Insa Hirschberg, Dario Brunetti, Indra Heckenbach, Morten Scheibye-Knudsen, Michela Deleidi.

Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal-glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPRmt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPRmt in neurodegenerative disease pathogenesis.

DOI: https://doi.org/10.1038/s41593-026-02320-1
Adv Sci (Weinh). 2026 Jun 22. e24167

Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4-Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR-Linked Pro-Clearance State.

Changxu Nie, Ruixi Yang, Xiaotong Wang, Ping Jia, Xueqi Zhang, Yaqi Dai, Xue Bai, Sijia Duan, Yufeng Li, Peng Zheng, Xin Tian, Li Jiang, Chao Wang.

  The mouse gene Lilrb4a, an ortholog of human leukocyte immunoglobulin-like receptor B4 (LILRB4), is markedly upregulated in microglia in Alzheimer's disease models and has been implicated in Apolipoprotein E (APOE)-related signaling. However, its contribution to amyloid pathology under an APOE4 background remains unclear. Here, 5xFAD mice carrying human APOE4 were used to assess the impact of Lilrb4a reduction by genetic deletion or antisense oligonucleotide treatment. Both approaches significantly reduced cortical amyloid plaque burden and APOE4-associated cerebral amyloid angiopathy without altering amyloid-β (Aβ) production. Bulk RNA sequencing identified enrichment of peroxisome proliferator-activated receptor (PPAR)-related and broader metabolic pathways in Lilrb4a-deficient mice. Consistently, biochemical analyses showed reduced p-SHP-2, NF-κB-p65, and p-STAT1, increased p-STAT3, and induction of anti-inflammatory and clearance-associated effectors, including Arg-1, TGF-β, and Cyp2e1. In primary microglia, pharmacological interrogation supported a functional contribution of PPAR-γ signaling to the enhanced Aβ uptake and degradation associated with Lilrb4a suppression, whereas PPAR-γ agonism recapitulated key pro-clearance phenotypes in vitro and attenuated amyloid pathology in vivo. Together, these data support Lilrb4a as an APOE4-associated microglial checkpoint candidate linked to impaired amyloid clearance and identify a PPAR-linked pro-clearance program as a potential downstream component of this response.

Keywords:  APOE4; LILRB4; Lilrb4a; PPAR‑γ; amyloid plaque; cerebral amyloid angiopathy; microglia

DOI:  https://doi.org/10.1002/advs.202524167
Adv Sci (Weinh). 2026 Jun 22. e76220

Biomimetic Hydrogel System Targeting S100A8 Centered Neuroimmune Crosstalk and Hypoxia Induced Neuronal Injury.

Peng Liu, Xiaoyang Wu, Xiaoyin Liu, Yuyan Wang, Shichao Jiang, Kai Wu, Gaowei Li, Jie Ding, Chengheng Wu, Dan Wei, Jing Sun, Hongsong Fan, Liangxue Zhou.

  Tissue hypoxia and neuroinflammation are major drivers of secondary injury after traumatic brain injury (TBI). S100A8, a pro-inflammatory damage-associated molecular pattern, is involved in pathological neuron-microglia signaling and may amplify secondary damage. However, effective interventions targeting S100A8-centered neuroimmune crosstalk remain lacking. Here, we developed a multifunctional biomimetic hydrogel system, HPC@Gel, by integrating modified hemoglobin nanoparticles and curcumin-based carbon quantum dots into a hyaluronic acid-collagen hydrogel to disrupt this vicious cycle. In vitro, hypoxic HT22 neurons, LPS-stimulated BV2 microglia, and an HT22-BV2 Transwell model were used to evaluate neuroprotection and neuroimmune regulation. HPC@Gel markedly downregulated S100A8 expression and attenuated pathological neuron-microglia crosstalk. Recombinant S100A8 rescue experiments further showed that exogenous S100A8 partially reversed the protective effects of HPC@Gel, supporting the functional role of S100A8 suppression. In a rat cortical cavity TBI model, HPC@Gel reduced S100A8 expression in neurons and microglia, alleviated neuronal hypoxia, and reversed neuroinflammation. These effects improved the pathological microenvironment, promoted endogenous neural regeneration, and facilitated neurological and cognitive recovery. This study provides a promising therapeutic strategy for TBI by simultaneously targeting hypoxia and S100A8-mediated neuroimmune crosstalk.

Keywords:  S100A8; TBI repair; biomimetic hydrogel; neuroimmune crosstalk

DOI:  https://doi.org/10.1002/advs.76220
Acta Neuropathol. 2026 Jun 25. pii: 72. [Epub ahead of print]151(1):

Donor-specific pathological features associate with genetic background, lesion type distribution, and clinical heterogeneity in multiple sclerosis.

Lukas Lütje, J Q Alida Chen, Jörg Hamann, Joost Smolders, Inge Huitinga, Aletta M R van den Bosch.

  Multiple sclerosis (MS) shows pronounced pathological and clinical variability between individuals, reflecting differences in genetic susceptibility, inflammatory activity, and tissue repair. This variability complicates efforts to relate lesion pathology to clinical trajectories. In previous work in the Netherlands Brain Bank MS autopsy cohort (NBB-MS), we showed that relative proportions of different lesion types, lesion load, and microglia/macrophage activity score, associate with clinical severity, while also revealing marked inter-individual variability. Here, we extend these observations by examining whether selected donor-specific pathological features relate to genetic background, quantitative lesion type distributions, and clinical disease course, and thereby help contextualize this heterogeneity.Brain tissue from 287 NBB-MS donors was assessed for the presence of the donor-specific pathological features, namely perivascular cuffs, microglial nodules, broad rim lesions (BRLs), and remyelination efficiency. Perivascular cuffs and microglial nodules were more prevalent among carriers of the MS susceptibility allele HLA-DRB1*15:01 (rs3135388). BRLs and perivascular cuffs were enriched in carriers of the MS severity-associated SNP in the DYSF-ZNF638 locus (rs10191329). Perivascular cuffs associated with increased microglia/macrophage activation score and decreased age at death. Microglial nodules in the normal appearing white matter associated with a higher proportion of active lesions. BRLs were linked to increased proportions of active and mixed active/inactive lesions, higher brainstem lesion rate, and a higher age related MS severity score. Poor remyelination efficiency associated with a higher proportion of mixed active/inactive and inactive lesions, and a shorter disease duration.Together, these findings show that specific pathological features of donors relate to genetic risk, lesion type distribution, and clinical outcome. Integrating these donor-specific pathological features alongside lesion classification will enable a more biologically refined interpretation of post-mortem MS tissue study results and will improve understanding of inter-individual heterogeneity in MS.

Keywords:  Broad rim lesions; Microglia nodules; Multiple sclerosis; Neuropathology; Perivascular cuffs; Remyelination

DOI:  https://doi.org/10.1007/s00401-026-03040-3
J Nanobiotechnology. 2026 Jun 25.

Targeting microglial circMBNL1 unlocks a novel nanomedicine therapeutic strategy for major depressive disorder.

Xiaoyu Yu, Yan Lu, Zhiren Tan, Shulei Gao, Long Ye, Xiaoyan Luo, Jian Xie, Yuhao Miao, Bing Wang, Chenrui Liang, Ying Liu, Jilong Wang, Yinchu Ma, Yingli Luo.

  Major depressive disorder (MDD) is a prevalent psychological disorder that has a substantial effect on social and psychological functioning, requiring innovative treatments. Circular RNAs (circRNAs) have been shown to play a role in the pathogenesis of MDD and represent promising therapeutic targets. However, the target delivery strategies of interfering circRNAs against depression have not been extensively researched. Here, CircMBNL1 was identified to be significantly upregulated in plasma samples and showed a positive correlation with 24-Hamilton Depression Scale (HAMD-24) scores in patients with MDD. Moreover, in the microglia of the brains of mice subjected to the chronic unpredictable stress (CUS) model, circMBNL1 was significantly upregulated. To achieve specific knockdown of circMBNL1 in microglia, PEG/PEI-based nanoparticles were modified with MG1 peptide for the targeted delivery of siRNA (TNP-si-circMBNL1) into activated microglia via intranasal administration. In vitro and in vivo studies demonstrated that TNP-si-circMBNL1 efficiently delivered si-circMBNL1 to activated microglia, resulting in a significant reduction in circMBNL1 expression. Notably, intranasal administration of TNP-si-circMBNL1 effectively ameliorated CUS-induced depressive-like behaviors in mice. These results indicate that circMBNL1 is linked to MDD, and the peptide-guided nanoparticle loaded siRNA targeting circMBNL1 (TNP-si-circMBNL1) displays great potential for depression therapy.

Keywords:  CircRNA; MDD; Microglia; Nanomedicine; Targeted Delivery

DOI:  https://doi.org/10.1186/s12951-026-04734-2
J Adv Res. 2026 Jun 21. pii: S2090-1232(26)00507-2. [Epub ahead of print]

Activation of microglial PPARγ by asperosaponin VI alleviates stress-induced depression and synaptic impairment.

Yangyan Ge, Chengyan Yang, Meidan Wang, Pei Liu, Zhihuang Zhao, Haili Zhang, Shuqin Lu, Hui He, Yan Fu, Chenghong Xiao, Tao Zhou, Zili You, Jinqiang Zhang.

   BACKGROUND: Depression is a common mental disorder affecting hundreds of millions worldwide. Targeting microglial peroxisome proliferator-activated receptor gamma (PPARγ) is regarded as one of the strategies to improve depression. However, a PPARγ activator capable of targeting brain microglia is currently lacking.
OBJECTIVES: To screen novel natural PPARγ agonists targeting brain microglia from phytomedicine and analyze their antidepressant mechanisms.
METHOD: Natural PPARγ agonists targeting brain microglia were identified from phytomedicine through molecular docking, kinetic simulations, surface plasmon resonance, and in vitro and in vivo approaches. The depression animal model was established using chronic unpredictable mild stress (CUMS). Depressive-like behaviors were evaluated using systematic behavioral analysis. Immunohistochemistry and Golgi staining were employed to evaluate the microglial phenotype and synaptic plasticity. The role of microglial PPARγ in improvement of neuroinflammation, synaptic impairment and depression was investigated in transgenic mice with conditional Pparg deletion in microglia.
RESULTS: A total of 18 potential compounds capable of activating microglial PPARγ were identified. Among them, asperosaponin VI (ASA-VI) showed stable binding affinity for multiple PPARγ subtypes and promoted PPARγ nuclear translocation in microglia. ASA-VI driven the phenotypic transformation of microglia toward a neuroprotective phenotype and inhibited neuroinflammation in vitro and in vivo. ASA-VI also improved hippocampal synaptic impairment and depressive-like behaviors in CUMS-exposed mice. Critically, conditional knockout of Pparg in microglia abolished the therapeutic effects of ASA-VI on neuroinflammation, synaptic impairment and depression.
CONCLUSION: Our findings identify ASA-VI as a microglial PPARγ activator that remodels microglial phenotype, suppresses neuroinflammation and alleviates stress-induced depression and synaptic impairment.

Keywords:  Asperosaponin VI; Microglia; Neuroinflammation; Peroxisome proliferator-activated receptorgamma; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.jare.2026.06.025
J Neuroinflammation. 2026 Jun 24. pii: 212. [Epub ahead of print]23(1):

Multi-dimensional decoding of the TSPO signal in animal models of neuroinflammation using fluorescence-conjugated DPA714.

Huanhuan Song, Zhibao Zhu, Limei Xiao, Qiuping Zhao, Chun Li, Aowei Lv, Xintong Yu, Zhuyu Gao, Jie Lin, Youliang Wang, Yuanyuan Zhang, Lijie Zhang, Runyun Li, Shaobo Yao, Mengchao Cui, Yi Lin, Ying Fu, V Wee Yong, Rui Li.



Keywords:  CSF1R; Microglia; Neuroinflammation; TSPO imaging probe; Translocator protein (TSPO)

DOI:  https://doi.org/10.1186/s12974-026-03829-9
J Neuroinflammation. 2026 Jun 25.

Immune checkpoint LAG-3 governs stage-dependent and disease-associated microglial modules in ALS model mice.

Yuta Morisaki, Nanaka Nomura, Motoki Ohshima, Miruto Matsuda, Okiru Komine, Takashi Okuda, Koji Yamanaka, Hidemi Misawa.

  Immune checkpoint molecules, inhibitory receptors originally characterized in T cell biology, have recently emerged as regulators of microglial function in neurodegeneration, yet their roles in amyotrophic lateral sclerosis (ALS) remain unexplored. Here, we investigated LAG-3, an inhibitory immune checkpoint receptor, in microglial regulation during ALS pathogenesis using SOD1G93A mice. LAG-3 expression was progressively upregulated in spinal cord microglia during disease progression, and LAG-3-high microglia exhibited a disease-associated microglia (DAM) transcriptional signature. Genetic deletion of LAG-3 produced a biphasic phenotype, with accelerated disease onset but significantly prolonged disease duration. LAG-3 deficiency enhanced inflammatory microglial responses at the early disease stage, whereas at the late stage it suppressed inflammatory signaling while selectively preserving phagocytic effector gene expression, demonstrating that LAG-3 dissociates the inflammatory and phagocytic modules within the DAM program in a stage-dependent manner. These transcriptional changes translated into enhanced phagocytic capacity in primary microglia and amelioration of the spinal cord environment through suppression of inflammatory pathways and restoration of oxidative phosphorylation. Our findings identify LAG-3 as a stage-dependent regulator of microglial functional states in ALS and support the concept that immune checkpoint molecules constitute a class of module-level regulators of microglial function in neurodegeneration.

Keywords:  Amyotrophic lateral sclerosis; Disease-associated microglia; Immune checkpoint; LAG-3; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1186/s12974-026-03919-8
Pharmacol Res. 2026 Jun 22. pii: S1043-6618(26)00228-8. [Epub ahead of print]230 108313

PIM1-induced Drp1 phosphorylation disrupts microglial mitophagy and aggravates neuroinflammation.

Xiaofang Liu, Lili Ma, Xueying Ma, Xiaomeng Ma, Xiqin Fang, Yingying Liu, Zhumin Su, Xiaoyun Liu, Zhiling Yu, Xiaohong Chen.

  Current disease-modifying therapies for multiple sclerosis (MS) primarily target peripheral immune responses but exhibit limited efficacy in mitigating the compartmentalized neuroinflammation driven by central nervous system (CNS)-resident microglia. By integrating clinical sample analysis with experimental autoimmune encephalomyelitis (EAE) model studies, we have demonstrated that the proviral integration site for Moloney murine leukemia virus 1 (PIM1) is significantly upregulated, particularly in microglia, in both MS patients and the spinal cords of EAE mice. This upregulation positively correlates with disease severity and levels of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6. Utilizing a multimodal research approach-including pharmacological inhibition (SMI-4a), genetic knockdown, RNA sequencing, and HIS-SIM super-resolution imaging-we confirmed that PIM1 inhibition effectively attenuates neuroinflammatory responses, improves clinical symptoms in EAE mice, and promotes activation of the mitophagy pathway while suppressing inflammation-related molecules. Mechanistically, PIM1 enhances the phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 while suppressing its phosphorylation at Ser637, which disrupts LC3-mitochondria colocalization and autophagosome-lysosome fusion. This leads to mitophagy dysfunction, loss of mitochondrial membrane potential, and accumulation of reactive oxygen species. Notably, the combined administration of PIM1 and Drp1 inhibitors did not yield synergistic therapeutic effects, suggesting that PIM1 likely functions as an upstream master regulator of Drp1. These findings not only elucidate the molecular mechanism by which PIM1 interacts with Drp1 to regulate microglial activation and mitophagy but also establish PIM1 as a promising CNS-intrinsic therapeutic target for restoring mitochondrial homeostasis in MS.

Keywords:  Lysosomal function; Microglia; Mitophagy; Multiple sclerosis; Neuroinflammation; PIM1

DOI:  https://doi.org/10.1016/j.phrs.2026.108313
Brain Behav Immun. 2026 Jun 21. pii: S0889-1591(26)00627-6. [Epub ahead of print]137 106879

Ventral striatal neuroimmune signalling biases the expression of social memory in male mice.

M Rinaudo, S Autelitano, C D'Amelio, I Nifo Sarrapochiello, G Puliatti, G Boni, R Sollazzo, D D Li Puma, F Paciello, F Natale, V Protto, G De Chiara, R Piacentini, S Fusco, C Grassi.

  Social behaviours are highly sensitive to inflammatory states. However, the precise contribution of neuroinflammation in the ventral striatum to social memory remains unclear. Using a mouse model of recurrent herpes simplex virus-1 (HSV-1) infection and a complementary model of region-restricted inflammation induced by bilateral intra-ventral striatum lipopolysaccharide (LPS) injection, we show that ventral striatal inflammation impacts social memory expression. Both HSV-1-infected and LPS-treated mice failed to discriminate between old and novel conspecifics, with LPS-treated animals showing a slight preference for the known stimulus. In these animals, social memory alterations were associated with microglial activation, inflammatory signalling, and increased GluA2 expression in the ventral striatum and were not dependent on altered social novelty sensitivity. In both models, behavioural alterations were rescued by dexamethasone treatment. Finally, LPS-induced neuroinflammatory markers in the ventral striatum correlated with preference for the familiar social stimulus. Together, these findings identify ventral striatal inflammation as a key modulator of social memory expression.

Keywords:  Dexamethasone; HSV-1; LPS; Microglia; Neuroinflammation; Social memory

DOI:  https://doi.org/10.1016/j.bbi.2026.106879
Cell Death Dis. 2026 Jun 22.

Astrocytic SCAP deletion ameliorates diabetes-associated cognitive impairment by suppressing microglial neuroinflammation and lipid droplet accumulation via the LCN2-24p3R-mTOR axis.

Kunyu Liu, Haoqiang Zhang, Wenwen Zhu, Tong Niu, Yonglian Hu, Haiping Zhou, Ruoyu Sun, Junru Zhou, Shaohua Wang, Yang Yuan.

Diabetes-associated cognitive impairment (DACI) is a prevalent and debilitating complication of type 2 diabetes, yet the mechanisms linking metabolic dysregulation to neuroinflammation and cognitive decline remain incompletely understood. In this study, we identify astrocytic SCAP (SREBP cleavage-activating protein) as a crucial regulator of glial metabolic-inflammatory crosstalk in DACI. Using a high-fat diet-induced mouse model of diabetes, we demonstrate that astrocytic SCAP expression is significantly upregulated, whereas astrocyte-specific SCAP deletion alleviates cognitive deficits, reduces microglial activation, and attenuates lipid droplet accumulation in the hippocampus. Transcriptomic analysis of SCAP-deficient mice identified lipocalin-2 (LCN2) as a prominent downstream candidate associated with inflammatory regulation. Mechanistically, astrocytic SCAP promotes NF-κB-dependent LCN2 expression, leading to LCN2-dependent paracrine activation of microglial 24p3R-mTOR signaling and consequent microglial inflammatory activation and lipid droplet accumulation. Consistently, pharmacological inhibition of mTOR or antibody-mediated blockade of LCN2 in vivo significantly ameliorated hippocampal neuroinflammation, neuronal injury, and cognitive decline in diabetic mice. These findings reveal a novel SCAP-LCN2-24p3R-mTOR signaling axis that links astrocytic lipid sensing to microglial inflammatory and metabolic dysfunction, providing a mechanistic framework for metabolic-inflammatory coupling in DACI and highlighting this pathway as a potential therapeutic target for DACI.

DOI: https://doi.org/10.1038/s41419-026-09019-y
Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00673-X. [Epub ahead of print]45(7): 117595

Divergent toxicity mechanisms of amyloid-beta aggregates arising from a single aggregation reaction.

Vanya Metodieva, Sybille Marchese, Pietro Esposito, John S H Danial, Andrea Di Falco, Suman De, David Klenerman, Juan A Varela.

  Amyloid-β 1-42 (Aβ42) aggregation is among the earliest pathological signs in Alzheimer's disease (AD). Here, we characterized Aβ42 species at several aggregation stages at the single-molecule level and examined their toxicity in murine organotypic brain slices, where we observed a stage-dependent recapitulation of multiple aspects of the cellular phase of AD. Aggregates formed during the lag phase of the Aβ42 aggregation elevated neuronal baseline Ca2+ levels and impaired long-term potentiation (LTP), while promoting microglial homeostatic exit and transition to disease-associated microglia (DAM) state. In contrast, aggregates enriched during the growth phase downregulated homeostatic microglial markers and induced TLR4-mediated microglial activation, cytokine production, and complement activation, leading to synaptic engulfment and severe disruption of neuronal activity. Together, these findings reveal that structurally distinct Aβ42 aggregate species engage different cellular and molecular pathways. This framework advances mechanistic understanding of amyloid toxicity in neurodegeneration and could inform the design of combination therapeutic strategies.

Keywords:  Alzheimer’s disease; CP: molecular biology; CP: neuroscience; DAM; TAK-242; TLR4; amyloid-beta; calcium imaging; inflammation; microglia; organotypic hippocampal slices; single-molecule imaging

DOI:  https://doi.org/10.1016/j.celrep.2026.117595
Stem Cell Res Ther. 2026 Jun 20.

Bone marrow mesenchymal stem cell-derived TSG-6 regulates microglial pyroptosis and alleviates bone cancer pain by inhibiting the NLRP3 inflammasome.

Danyang Xu, Mengna Jiang, Hao Ming, Jing Zhang, Yunqi Li, Ping Wu, Qingping Wen.

   BACKGROUND: The central sensitization mechanism of bone cancer pain is related to neuroinflammation, glial cell activation, and an acidic environment. Among them, the NLRP3 inflammasome is involved in the occurrence of bone cancer pain. Studies have shown that an intrathecal injection of bone marrow mesenchymal stem cells (BMSCs) alleviates bone cancer pain by inhibiting microglial cell activation. Upon inflammatory stimulation, BMSCs produce increased levels of Tumor necrosis factor-α-stimulated gene 6 (TSG-6), which regulates intercellular signaling and inflammatory responses; however, whether the secretion of TSG-6 from BMSCs inhibits NLRP3-mediated microglial pyroptosis to alleviate bone cancer pain is unknown. Therefore, this study aimed to evaluate the analgesic effect of TSG-6 released by BMSCs on bone cancer pain (BCP) and explore its potential mechanisms through in vitro and in vivo experiments.
METHODS: In vivo, Walker 256 breast cancer cells were injected into the bone marrow cavity of the left tibia of rats to establish a BCP model. On days 7 and 14 after surgery, intrathecal injections of BMSCs or exogenous recombinant TSG-6 were administered, and the analgesic effects were observed at 2, 4, 8, 24, and 48 h after administration. Spinal cord tissues were collected for Western blotting and immunofluorescence staining to assess the activation of the NLRP3 signaling pathway. In vitro, BV2 microglia were cocultured with BMSCs or recombinant TSG-6, and the same detection methods were performed to evaluate changes in the levels of proteins involved in the NLRP3 signaling pathway. BMSCs transfected with TSG-6-targeting shRNA were intrathecally injected in vivo or cocultured with microglia in vitro to investigate whether TSG-6 is involved in the inhibition of microglial pyroptosis and the inflammatory response mediated by BMSCs to alleviate BCP.
RESULTS: BMSC transplantation or treatment with exogenous recombinant TSG-6 significantly improved BCP-related behaviors, inhibited the expression of key proteins in the NLRP3 signaling pathway in spinal dorsal horn microglia in rats, and reduced the release of inflammatory factors. Experiments revealed that coculturing BMSCs with BV2 microglia or treating BV2 cells with exogenous recombinant TSG-6 inhibited the LPS-induced activation of NLRP3 in BV2 cells and regulated microglial pyroptosis. Transfection of BMSCs with TSG-6-targeting shRNA significantly weakened the inhibitory effect on microglial pyroptosis.
CONCLUSION: In vivo and in vitro experiments revealed that bone marrow mesenchymal stem cells inhibit the NLRP3 signaling pathway to regulate the pyroptosis of microglia through the secretion of TSG-6, thereby alleviating bone cancer pain.

Keywords:  Bone cancer pain (BCP); Bone marrow mesenchymal stem cells (BMSCs); Microglia; NLRP3; Pyroptosis; Tumor necrosis factor-α-stimulated gene 6 (TSG-6)

DOI:  https://doi.org/10.1186/s13287-026-05121-2
J Headache Pain. 2026 Jun 23.

Gnao1 acts as a gatekeeper to alleviate neuropathic pain by silencing pro-nociceptive signaling cascades.

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

   BACKGROUND: Neuropathic pain is a debilitating condition with limited effective treatments, highlighting an urgent need for non-opioid analgesic targets. Gαo, encoded by the Gnao1 gene, is an abundant G protein in the nervous system and couples to multiple inhibitory GPCRs, but its role in chronic pain remains poorly understood.
METHODS: Spatial transcriptomics and bulk RNA-sequencing were performed on the spinal cord and dorsal root ganglia (DRG) of mice following spared nerve injury (SNI). Adeno-associated virus (AAV)-mediated Gnao1 overexpression or knockdown was performed in the spinal cord or DRG, followed by pain behavioral testing using von Frey filaments, acetone evaporation test, and mechanical conflict avoidance (MCA) assay. Microglial activation, neuronal injury, and signaling pathways were examined by immunohistochemistry (IHC), Western blotting (WB), and calcium imaging. In vitro studies used BV2 microglia and primary DRG neurons with lentiviral Gnao1 overexpression and LPS or db-cAMP stimulation.
RESULTS: Spatial transcriptomics revealed that Gnao1 is enriched in the spinal dorsal horn (SDH) and significantly downregulated after SNI. Bulk RNA-seq confirmed Gnao1 downregulation in pain-processing regions (DRG and SDH). IHC showed that its cellular localization shifted from neurons to glial cells. Overexpression of Gnao1 in the spinal cord or DRG markedly alleviated SNI-induced mechanical allodynia, cold hypersensitivity, and pain-related avoidance behaviors. Mechanistically, transcriptomic profiling revealed that Gnao1 overexpression broadly suppressed pro-inflammatory and pro-nociceptive pathways. Experimental validation confirmed that Gnao1 overexpression reduced p38, ERK, and NF-κB phosphorylation, and decreased microglial activation. In primary DRG neurons, Gnao1 overexpression also lowered cAMP levels and suppressed db-cAMP-evoked Ca2+ influx.
CONCLUSION: Gnao1 acts as a gatekeeper negative regulator of neuropathic pain by silencing distinct pro-nociceptive signaling cascades, and highlights its potential as a non-opioid analgesic target.
CLINICAL TRIAL NUMBER: Not applicable.

Keywords:  Gnao1; Neuroinflammation; Neuropathic pain; Pro-nociceptive signaling; RNA-sequencing; Spared nerve injury; Spatial transcriptomics

DOI:  https://doi.org/10.1186/s10194-026-02436-6
Phytomedicine. 2026 Jun 17. pii: S0944-7113(26)00681-1. [Epub ahead of print]159 158450

Oxymatrine alleviates cerebral ischemia-reperfusion injury by inhibiting microglia ferroptosis via NRF2 pathway activation.

Nanding Wu, Yutong Wang, Mengjie Guo, Ruili Ran, Dewei Wang, Junqiu Song, Lishan Hui, Jing Yang, Yue Yang.

   BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) involves secondary damage following blood flow restoration. Ferroptosis, an iron-dependent cell death process, is implicated in CIRI, with mitochondrial dynamics imbalance playing a critical role. Oxymatrine (OMT), a quinolizidine alkaloid extracted from the root of Sophora flavescens, exhibits neuroprotective properties, yet its role in modulating microglia ferroptosis and mitochondrial homeostasis during CIRI remains unclear.
PURPOSE: This study aimed to investigate whether OMT attenuates microglia ferroptosis in CIRI by activating the nuclear factor erythroid 2-related factor 2 (NRF2) pathway and restoring mitochondrial dynamic balance.
METHODS: Using a rat middle cerebral artery occlusion/reperfusion model and BV-2 microglia under oxygen-glucose deprivation/reoxygenation, we evaluated the effects of OMT alone or with NRF2 inhibitor ML385 or ferroptosis inducer Erastin. Assessments included neurological scores, infarct volume, Reactive Oxygen Species, ferrous iron, malondialdehyde, glutathione, mitochondrial membrane potential, and related protein expression, including NRF2, kelch-like ECH-associated protein 1 (KEAP1), heme oxygenase-1, solute carrier family 7 member 11, ferritin heavy chain, glutathione peroxidase 4, dynamin-related protein 1, optic atrophy 1. Molecular docking, surface plasmon resonance, and co-immunoprecipitation were used to examine OMT-KEAP1 binding. Finally, in vitro rescue experiments using KEAP1 overexpression and CDDO-ME (a specific KEAP1 inhibitor) confirmed the KEAP1/NRF2 dependency by re-assessing cell viability and ferroptosis markers.
RESULTS: OMT improved neurological outcomes and suppressed ferroptosis in vivo and in vitro. Mechanistically, OMT disrupted KEAP1-NRF2 binding, promoting NRF2 nuclear translocation and upregulating solute carrier family 7 member 11, heme oxygenase-1, ferritin heavy chain, and glutathione peroxidase 4. This restored mitochondrial homeostasis by balancing optic atrophy 1 and dynamin-related protein 1, thereby reducing lipid peroxidation. Crucially, these effects were abolished by ML385 or Erastin, while KEAP1 overexpression and CDDO-ME respectively mimicked KEAP1-mediated suppression and NRF2-driven protection. These findings confirm OMT acts via a KEAP1/NRF2-dependent anti-ferroptotic axis.
CONCLUSIONS: OMT protects against CIRI by inhibiting microglia ferroptosis through NRF2 pathway activation and improvement of mitochondrial homeostasis, supporting its potential as a therapeutic agent for ischemic stroke.

Keywords:  Cerebral ischemia-reperfusion injury; Ferroptosis; Microglia; Mitochondrial dynamics; Oxymatrine

DOI:  https://doi.org/10.1016/j.phymed.2026.158450
JCI Insight. 2026 Jun 22. pii: e197980. [Epub ahead of print]11(12):

Microglial SWELL1 deficiency drives male-specific seizure vulnerability but paradoxical neuroprotection through impaired phagocytosis.

Abhijeet S Barath, Aastha Dheer, Laura Montier, Mekenzie M Peshoff, Emily Dale, Flavia Goche, Thanh Thanh Le Nguyen, Mastura Akter, FangFang Qi, Dimitrios Kleidonas, Lauren Harris, Sarah A Jewanee, Anthony D Umpierre, Dale B Bosco, Koichiro Haruwaka, Rajan Sah, Long-Jun Wu.

  The discovery of genes encoding the volume-regulated anion channel (VRAC) has enabled detailed exploration of its cell type-specific roles in the brain. LRRC8A (SWELL1) is the essential VRAC subunit. We observed seizure-induced, subunit-specific changes in microglial VRAC expression and investigated its function using conditional KO (cKO) of LRRC8A in microglia. SWELL1 cKO mice exhibited a male-specific increase in kainate-induced seizure severity, yet showed paradoxical neuroprotection against seizure-associated neuronal loss. Mechanistically, SWELL1 deletion led to a cell-autonomous reduction in microglial density and decreased release of VRAC-permeable neuroactive metabolites, including taurine, GABA, and glutamate in culture. Additionally, impaired phagocytic kinetics and reduced lysosomal biogenesis contributed to the observed neuroprotection. These findings reveal potentially novel roles for microglial VRAC in regulating seizure outcomes and microglia-neuron interactions.

Keywords:  Epilepsy; Immunology; Neuroscience; Seizures

DOI:  https://doi.org/10.1172/jci.insight.197980
Cell Biol Toxicol. 2026 Jun 25.

GPNMB regulates EGFR mitochondrial translocation via HK2, influencing microglial respiratory chain and metabolic defects to promote polarization and stroke progression.

Chang Gao, Qiong Nie, Yongnan Hao, Hongqiang Song, Cui-Cui Zhang.

   BACKGROUND: One of the main reasons of disability and death is stroke in China and other countries, with growing evidence pointing to the role of microglial polarization in its pathogenesis. Epidermal growth factor receptor as well as Glycoprotein non-metastatic melanoma protein have been implicated in cellular signaling pathways relevant to microglial function. However, the mechanism by which GPNMB regulates EGFR signaling and its impact on mitochondrial translocation and polarization remains unclear.
METHODS: We established middle cerebral artery occlusion model in mice to investigate GPNMB expression and its role in microglial activation. Various experimental techniques, including TTC staining, western blotting, Nissl staining, H&E staining, immunofluorescence, and flow cytometry, were employed to assess cellular changes and molecular interactions. Furthermore, the effects of GPNMB on energy metabolism were evaluated through ATP assays and mitochondrial membrane potential assessments.
RESULTS: Upregulated GPNMB was observed in microglia following MCAO. GPNMB Inhibition resulted in reduced infarct volume, diminished neuronal damage, and altered microglial polarization towards the anti-inflammation phenotype. Additionally, GPNMB was found to regulate EGFR translocation, which in turn influenced HK2 expression, thereby affecting mitochondrial function and energy metabolism in microglia. Expression of respiratory-chain proteins (CYTB, MTCO2, ATP6) was increased following GPNMB inhibition. The use of EGFR activators and inhibitors further confirmed the critical role of this signaling pathway in mediating GPNMB's effects.
CONCLUSION: In conclusion, GPNMB regulates mitochondrial translocation of ERGR via HK2, influencing microglial respiratory chain and metabolic defects to promote stroke progression.

Keywords:  ERGR; GPNMB; Microglial; Mitochondrial dysfunction; Stroke

DOI:  https://doi.org/10.1007/s10565-026-10215-x
J Transl Med. 2026 Jun 25.

Integrative transcriptomic analysis identifies meningeal-hippocampal immune communication in Alzheimer's disease.

Congcong Yan, Zhoushuai Chen, Yi Yan, Miao Wang, Wenting Chen, Feifan Zhou, Qian Liu.

   BACKGROUND: Alzheimer's disease (AD) exhibits spatial heterogeneity, yet the mechanisms by which immune-active meninges communicate with vulnerable brain regions during disease progression remain unclear. This study aimed to investigate meninges-hippocampus crosstalk and map the communication patterns during AD pathology development.
METHODS: We employed 5xFAD transgenic and PS19 tau-pathology mouse models and integrated bulk RNA sequencing, proteomics, and spatial transcriptomics across time-course analyses to distinguish AD pathology from normal aging processes. Transcription factor activity inference was coupled with ligand-receptor dynamics analysis to examine regulatory modules in homeostatic and disease-associated microglia.
RESULTS: We identified structure-specific disease genes, including a robust 19-gene hippocampal signature that was reproducible across an independent 5xFAD dataset and PS19 tau-pathology dataset. Spatial analysis defined a disease progression axis that transferred to the independent spatial dataset, where meningeal spots were enriched in advanced disease progression layers and disease modules showed consistent gradients. Ligand-receptor and microglial-state LRaxis analyses further supported candidate communication axes associated with pathology gradients and state-specific regulatory modules in both homeostatic and disease-associated microglia.
CONCLUSIONS: Our spatial framework supports the meninges as a candidate modulatory interface associated with hippocampal pathology in AD mouse models. These mouse-derived, computationally inferred ligand-receptor and regulatory modules should be considered hypothesis-generating candidates that require validation in human AD tissues and functional perturbation studies before translational relevance can be inferred.

Keywords:  Alzheimer’s disease; Ligand-receptor signaling; Meninges; Microglia

DOI:  https://doi.org/10.1186/s12967-026-08414-5
Cell Death Discov. 2026 Jun 24.

Inhibition of HSPA8 alleviates experimental autoimmune encephalomyelitis via dual modulation of NLRP3 inflammasome activation: suppressing both NF-κB-mediated priming and ASC-dependent assembly.

Qianqian Bai, Yan Guo, Shunji Pan, Fangfei Liu, Wenchao Tang, Xiaozhi Bai, Shumin Zhang, Xiaoyu Ma, Qizhi Fu, Dongmei Wang, Hua Fan.

The pathological processes of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are closely associated with excessive activation of inflammasomes. HSPA8 is a constitutively expressed molecular chaperone involved in cellular signaling and immune-inflammatory regulation, but its role in EAE-associated neuroinflammation remains unclear. In this study, we found that HSPA8 was significantly upregulated in the spinal cord tissues of EAE mice and positively correlated with disease severity. Immunofluorescence co-staining showed that HSPA8 upregulation was more prominently associated with Iba1-positive microglia/macrophage-enriched regions than with GFAP- or NeuN-positive regions. Intrathecal knockdown of HSPA8 attenuated EAE progression, reduced inflammatory responses, and alleviated demyelination and axonal injury. In vitro, HSPA8 knockdown reduced NLRP3 inflammasome-mediated IL-1β/IL-18 release, caspase-1 activation, GSDMD-N formation, and pyroptosis in THP-1 cells, bone marrow-derived macrophages, and BV2 microglia, and these effects were partially restored by siRNA-resistant HSPA8 rescue. Mechanistically, HSPA8 knockdown was associated with impaired NF-κB-dependent priming, as reflected by reduced p65 phosphorylation, nuclear translocation, NF-κB transcriptional activity, and pro-IL-1β expression. HSPA8 is also associated with ASC, and HSPA8 knockdown impaired NLRP3-ASC interaction, ASC oligomerization, and ASC speck formation during inflammasome assembly. These findings suggest that HSPA8 is functionally associated with NLRP3 inflammasome activation through both NF-κB‑dependent priming and ASC‑associated assembly, thereby contributing to neuroinflammation in EAE. HSPA8 may represent a potential therapeutic target for MS-related and other inflammasome-driven neuroinflammatory disorders.

DOI: https://doi.org/10.1038/s41420-026-03215-7
Neural Regen Res. 2026 Jun 20.

Time-resolved single-nucleus profiling of inter- and intracellular signaling in optic nerve injury: From the hyperacute phase to the acute phase.

Yi Ding, Wenyue Zhang, Yeli Deng, Lunhao Li, Ping Gu, Leilei Zhang, Kwok-Fai So, Caiwen Xiao.

  Optic nerve injury induces rapid retinal neurodegeneration; however, how distinct retinal cell type responses are coordinated from the hyperacute injury phase to the early repair phase remains incompletely understood. In this study, to explore the dynamic changes in intercellular and intracellular signaling events between different cell types and elucidate their potential roles in retinal ganglion cell survival and early repair, we generated a time-resolved single-nucleus RNA sequencing atlas of adult male mouse retinas across five hyperacute-to-acute timepoints (2 hours, 8 hours, 1 day, 3 days, and 7 days) following optic nerve injury. Using computational network analysis, we reconstructed dynamic cell-to-cell communication and subsequent internal genetic responses among retinal ganglion cells, Müller glia, microglia, and endothelial cells. Distinct stage-specific intercellular communication networks were identified, including transient Itgb1-associated signaling between Müller glia and retinal ganglion cells that peaked at early timepoints, enhanced Nrxn1-Nlgn1-mediated signaling in endothelial cells during the acute phase, and sustained Sema6a-Plxna4 interactions in microglia through day 7. Functional pathway analysis linked these signaling events to focal adhesion, energy metabolism, immune regulation, and cell adhesion pathways. Multiplex immunofluorescence further validated the temporal dynamics and spatial localization of key signaling molecules, including Itgb1, Nlgn1, and Plxna4, consistent with the transcriptomic findings. Collectively, these results delineate a coordinated hyperacute-to-acute neuro-glial-vascular signaling network that supports retinal ganglion cell survival and identify potential molecular targets for therapeutic intervention following optic nerve injury.

Keywords:  Müller glia; endothelial cell; integrin β1; microglia; neuroligin 1; neuro–glial–vascular interaction; optic nerve injury; plexin A4; retinal ganglion cell; single-nucleus RNA sequencing

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01953