bims-microg 2025-10-19 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–10–19
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Atypical antipsychotics alter microglial functions via astrocyte-derived extracellular vesicles.
C9orf72 hexanucleotide repeat expansions impair microglial response in ALS.
Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles.
Microglia-specific regulation of lipid metabolism in Alzheimer's disease revealed by microglial depletion in 5xFAD Mice.
Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia.
Integrated single-cell multiomic profiling of caudate nucleus suggests key mechanisms in alcohol use disorder.
Elevated Apolipoprotein E Expression in Hippocampal Microglia Drives Temporal Lobe Epilepsy Progression.
Pharmacological Microglial Inhibition Remodels the Scar Microenvironment to Support Reticulospinal Circuit Reconstruction After Spinal Cord Injury.
Exosomes miR-369-3p Alleviates Early Brain Injury After Subarachnoid Hemorrhage by Promoting Ferroptosis of M1 Microglia via Inhibiting iNOS/GPX4 Axis.
PET-MRI biomarkers reveal efficacy of a novel NLRP3 inhibitor in Parkinson's disease models.
VU0360172 exerts anti-inflammatory effect on germinal matrix hemorrhage in neonatal rats via the mGluR5/PI3Kγ/PPARγ pathway.
Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Cognitive Decline by Restoring Senescent Microglial Function via NF-κB-SREBP1 Pathway Inhibition.
Pro-inflammatory S100A9 contributes to retinal ganglion cell degeneration in glaucoma.
Akkermansia muciniphila alleviates cognitive impairment and neuroinflammation induced by blunt chest trauma.
Ablation of progranulin augments microglial activation and accelerates prion progression.
Circulating plasma exosomal miR-146b-5p regulates microglial-mediated neuroinflammation through the TRAF6/NF-κB signaling axis after intracerebral hemorrhage.
Synaptic dysfunction and glial activation markers throughout aging and early neurodegeneration: a longitudinal CSF biomarker-based study.
Retinal degeneration driven by brain-derived neurotrophic factor deficiency in microglia and T-lymphocytes.
OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies.
Neuroinflammatory Human Brain Organoids Enable Comprehensive Drug Screening Studies: Fingolimod and its Analogues in Focus.

Brain Behav Immun. 2025 Oct 10. pii: S0889-1591(25)00374-5. [Epub ahead of print]131 106132

Atypical antipsychotics alter microglial functions via astrocyte-derived extracellular vesicles.

Hana Yeh, Yoonjae Song, Joshua J Bowen, Liam T McCrea, Steven D Sheridan, Roy H Perlis.

  A limited understanding of the underlying molecular mechanisms of atypical antipsychotics has hindered efforts to develop the next generation of treatments for schizophrenia. In particular, there has been little investigation of how medications like clozapine and olanzapine modulate human non-neuronal cells, including astrocytes and microglia. Recent postmortem and serum-based studies suggest that schizophrenia etiology involves dysregulated cellular communication through extracellular vesicles (EVs). Astrocytes are a major source of these EVs and are strongly implicated in the etiology of schizophrenia by convergent data from human postmortem, brain imaging, RNA-sequencing, and genome-wide association studies. We hypothesized that clozapine and olanzapine can affect microglia biology indirectly via astrocytic secretion of EVs. We used in vitro cellular models with human astrocytes and PBMC-derived microglial-like cells to investigate the downstream impact of isolated astrocyte-derived EVs (ADEVs) on microglial phenotypes relevant to schizophrenia, including microglial phagocytosis, motility, and morphology. To model microglia-mediated synaptic pruning in vitro, we utilized image-based quantification of microglia engulfment of isolated human synaptosomes. We found that treatment with ADEVs reduced microglial synaptosome phagocytosis in a dose-dependent manner. This reduction was reversed upon addition of ADEVs isolated from astrocytes treated with norclozapine or olanzapine. ADEVs isolated from clozapine-treated astrocytes increased microglial motility, indicating that clozapine alters microglial surveillance activity without affecting phagocytosis through these ADEVs. Together, these results suggest that atypical antipsychotics have distinct and indirect impact on microglia biology mediated by ADEVs. These results highlight a potentially critical role for ADEVs in regulating glial cell communication, and suggest they may be promising therapeutic targets for next-generation antipsychotic development.

Keywords:  Astrocytes; Atypical antipsychotics; Glia; Microglia; Neuroinflammation; extracellular vesicles (EVs)

DOI:  https://doi.org/10.1016/j.bbi.2025.106132
Nat Neurosci. 2025 Oct 14.

C9orf72 hexanucleotide repeat expansions impair microglial response in ALS.

Pegah Masrori, Baukje Bijnens, Laura Fumagalli, Kristofer Davie, Suresh Kumar Poovathingal, Tim Meese, Annet Storm, Nicole Hersmus, Raheem Fazal, Diede van den Biggelaar, Bob Asselbergh, Roxane Gruel, Johanna Van Den Daele, Heidi Denton, Paula Polanco Miquel, Simona Manzella, Winnok H De Vos, Siddhartan Chandran, Ludo Van Den Bosch, Dietmar Rudolf Thal, Renzo Mancuso, Philip Van Damme.

Microglia and neuroinflammation are involved in amyotrophic lateral sclerosis (ALS), but the precise underlying molecular mechanisms remain elusive. We generated single-nuclei transcriptomes from the spinal cord and motor cortex of patients with sporadic ALS (sALS) and C9orf72 ALS (C9-ALS). Here we confirmed that C9orf72 is highly expressed in microglia and observed that the hexanucleotide repeat expansion (HRE) results in haploinsufficiency. Whereas sALS microglia transitioned toward disease-associated cell states, C9orf72 HRE microglia exhibited a diminished response, with alterations in endolysosomal pathways. We confirmed these observations using a human microglia xenograft model, in which C9orf72 mutations led to a reduced activation. We also confirmed the endolysosomal alterations in C9orf72 HRE and C9orf72-deficient induced pluripotent stem cell (iPSC)-derived microglia. We also found a diminished response of C9orf72 HRE astrocytes and provided a map of dysregulated ligand-receptor pairs in microglia and astrocytes. Our data highlight variations in the cellular substrate of sporadic and inherited forms of ALS, which have implications for patient stratification and selection of appropriate treatments.

DOI: https://doi.org/10.1038/s41593-025-02075-1
Sci Transl Med. 2025 Oct 15. 17(820): eadq3401

Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles.

Yuichiro Itoh, Noriko Itoh, Sophia Wendin, Nadya Higgins, Rhonda R Voskuhl.

Women are more susceptible to multiple sclerosis (MS) than men, with a reported incidence ratio of ~3:1. Kdm6a is an X-chromosomal gene that escapes X inactivation, leading to higher expression of the histone demethylase KDM6A in females compared with males. Here, we focused on the role of Kdm6a in microglia in MS because this cell type plays a key role in the neuropathology of MS. Kdm6a was selectively deleted from microglia in experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. Deletion of Kdm6a in microglia ameliorated pathology, reduced the expression of disease-associated markers, increased the expression of resting microglial markers, and reversed other translatome changes in spinal cord tissues of female EAE mice. Deletion of Kdm6a in microglia had only very minor effects on EAE in male mice. The diabetes medicine metformin, which also blocks KDM6A's histone demethylase activity, ameliorated EAE in females, but not males, and normalized translatome profiles in microglia. CUT&RUN and sequencing analysis of microglial nuclei identified genes bound by KDM6A. When combined with translatomic analysis, this revealed correspondence between KDM6A protein binding and gene expression changes. Transcriptomic analysis of human microglia confirmed the higher expression of KDM6A in women compared with men and revealed that more microglial genes were dysregulated in women than in men with MS. Our results suggest that KDM6A might contribute to sex differences in susceptibility to MS.

DOI: https://doi.org/10.1126/scitranslmed.adq3401
Nat Commun. 2025 Oct 15. 16(1): 9156

Microglia-specific regulation of lipid metabolism in Alzheimer's disease revealed by microglial depletion in 5xFAD Mice.

Ziying Xu, Sepideh Kiani Shabestari, Savannah Barannikov, Kevin F Bieniek, Mathew Blurton-Jones, Juan Pablo Palavicini, Xianlin Han.

Abnormal lipid metabolism is observed in Alzheimer's disease (AD), but its contribution to disease progression remains unclear. Genetic studies indicate that microglia, the brain's resident immune cells, influence lipid processing during AD. Here, we show that microglia-the brain's resident immune cells-selectively regulate lipid accumulation that associated with disease pathology in both AD mouse models and human postmortem brains. Using lipidomics and histological analysis, we identify a striking buildup of arachidonic acid-containing bis(monoacylglycero)phosphate in response to amyloid plaques, which depends on microglial activity and the AD risk gene GRN. In contrast, lysophosphatidylcholine and lysophosphatidylethanolamine accumulate independently of microglia, correlating instead with astrocyte activation and oxidative stress. These results connect dysregulated lipid metabolism in AD to distinct brain cell types and molecular pathways. Our findings highlight microglial lipid homeostasis as a potential therapeutic target for modifying disease progression in AD.

DOI: https://doi.org/10.1038/s41467-025-64161-z
Nat Commun. 2025 Oct 14. 16(1): 9123

Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia.

Alyssa M Wilson, Michelle M Jacobs, Tova Y Lambert, Aditi Valada, Gregory Meloni, Evan Gilmore, Jacinta Murray, Susan Morgello, Schahram Akbarian.

For people with HIV, substance use disorders are a prominent neurological risk factor, and the impacts of both on dopaminergic pathways may pose a deleterious convergence. Here, we profile, at single nucleus resolution, substantia nigra transcriptomes of 90 postmortem donors in the context of chronic HIV and opioid/cocaine use disorders, including 67 prospectively characterized people with HIV. We report altered microglial expression for hundreds of pro- and anti-inflammatory regulators attributable to HIV, and separately, to opioid/cocaine disorders. Stepwise, progressive microglial dysregulation coupled to altered dopaminergic/GABAergic signaling is associated with substance/HIV dual diagnosis, and further with lack of viral suppression in blood. In suppressed donors, opioid/cocaine comorbidity is associated with microglial transcriptional changes permissive for HIV infection. Finally, HIV-related downregulation of monoamine reuptake transporters emerges specifically in dopaminergic neurons regardless of substance use disorder status or viral load, as do transcriptional signatures consistent with selective vulnerability of dopamine neurons.

DOI: https://doi.org/10.1038/s41467-025-64193-5
Nat Commun. 2025 Oct 13. 16(1): 9070

Integrated single-cell multiomic profiling of caudate nucleus suggests key mechanisms in alcohol use disorder.

Nicholas C Green, Hongyu Gao, Xiaona Chu, Qiuyue Yuan, Patrick McGuire, Dongbing Lai, Guanglong Jiang, Xiaoling Xuei, Jill L Reiter, Julia Stevens, Greg T Sutherland, Alison M Goate, Zhiping P Pang, Paul A Slesinger, Ronald P Hart, Jay A Tischfield, Arpana Agrawal, Yue Wang, Zhana Duren, Howard J Edenberg, Yunlong Liu.

Alcohol use disorder (AUD) induces complex transcriptional and regulatory changes across multiple brain regions including the caudate nucleus, which remains understudied. Using paired single-nucleus RNA-seq and ATAC-seq on caudate samples from 143 human postmortem brains, including 74 with AUD, we identified 17 distinct cell types. A significant portion of the alcohol-related differences in gene expression were accompanied by a corresponding difference in chromatin accessibility within the gene. We observed transcriptional differences in medium spiny neurons that impact RNA metabolism and immune response pathways. A small cluster of D1/D2 hybrid neurons showed AUD-induced differences distinct from the D1 and D2 types, suggesting a unique role in AUD. Those with AUD had a higher proportion of microglia in an inflammatory state; astrocytes entered a reactive state partially regulated by JUND. Oligodendrocyte dysregulation was driven in part by OLIG2 activity and increased TGF-β1 signaling from microglia and astrocytes. We also observed increased microglia-astrocyte communication via the IL-1β pathway. These findings provide valuable insights into the genetic and cellular mechanisms in the caudate related to AUD. They also demonstrate the broader utility of large-scale multiomic studies in uncovering complex gene regulation across diverse cell types, which has implications beyond the substance use field.

DOI: https://doi.org/10.1038/s41467-025-64136-0
Adv Sci (Weinh). 2025 Oct 14. e05778

Elevated Apolipoprotein E Expression in Hippocampal Microglia Drives Temporal Lobe Epilepsy Progression.

Jianwei Shi, Zesheng Li, Xin Sun, Yanfeng Yang, Yumin Luo, Ziang Song, Hengxin Dong, Lei Jin, Jing Xie, Yongzhi Shan, Guoguang Zhao.

  Temporal lobe epilepsy (TLE), the most common form of epilepsy, is primarily characterized by hippocampal sclerosis (HS). Microglia reactivity is a critical component of TLE pathogenesis, and apolipoprotein E (APOE) may be a potential mediator of these processes. However, its role in TLE progression remains unclear. Bioinformatics approaches with biomarker validation are integrated to elucidate APOE's role and hippocampal microglia in the mechanisms underlying TLE. APOE expression is significantly elevated in the hippocampal tissues of patients with TLE-HS and in TLE mouse models. Single-cell RNA sequencing reveals a subset of microglia with high APOE gene expression, which serves as the principal carrier of increased APOE during disease progression. Bioinformatic analyses, in vitro studies, and in vivo functional experiments utilizing TLE mouse models implicate these APOE-expressing microglia in regulating microglial differentiation, promoting neuroinflammation, neuronal apoptosis, and enhancing neuronal excitability. Genetic knockout of APOE mitigates gliosis, neuronal cell death, and seizure frequency in the hippocampus of epileptic mice. Additionally, APOE expression primarily induces significant alterations in glycerophospholipid metabolism and its associated metabolic derivatives within the epileptic microenvironment. Overall, APOE-expressing microglia are pivotal drivers of HS and TLE progression, positioning APOE and its downstream signaling pathways as promising therapeutic TLE targets.

Keywords:  apolipoprotein E; metabolomics; microglia; neuroinflammation; neuronal excitability; temporal lobe epilepsy

DOI:  https://doi.org/10.1002/advs.202505778
Adv Sci (Weinh). 2025 Oct 17. e03966

Pharmacological Microglial Inhibition Remodels the Scar Microenvironment to Support Reticulospinal Circuit Reconstruction After Spinal Cord Injury.

Run Li, Hongyuan Xing, Yifan Shen, Meng Chen, Bowen Lyu, Xiaofeng Yang, Li Sun, Chao Jiang, Jianyu Lv, Xin Ding, Zhongyang Gao, Yue Wang.

  Due to an inhibitory scar microenvironment that prevents neural circuit reconstruction, spinal cord injury (SCI) often leads to persistent neurological dysfunction. Although neonatal murine models demonstrate that microglial inhibition enables scar remodeling to support neuroregeneration and functional recovery, effective pharmacological suppression of microglial activation in adult SCI remain elusive. Here, this work demonstrates that early β2-adrenergic receptor agonist treatment drives microglial transition to a homeostatic phenotype within the post-SCI scar. This intervention reduces inhibitory extracellular matrix deposition and transforms the inhibitory microenvironments into permissive substrates for axonal regrowth. Anatomical analyses reveal regeneration of the reticulospinal tract, which establishes synaptic connectivity with thoracolumbar circuits to mediate motor recovery in a complete SCI. These findings elucidate the therapeutic potential and neural circuit mechanisms underlying pharmacological microglial modulation for SCI repair, establishing a glial-neural circuit reparative paradigm.

Keywords:  microglial inhibition; motor function recovery; reticulospinal tract; spinal cord injury; Î22‐adrenergic receptor

DOI:  https://doi.org/10.1002/advs.202503966
Brain Behav. 2025 Oct;15(10): e70966

Exosomes miR-369-3p Alleviates Early Brain Injury After Subarachnoid Hemorrhage by Promoting Ferroptosis of M1 Microglia via Inhibiting iNOS/GPX4 Axis.

Jian Fang, Feiyun Qin, Pengcheng Xu, Xintong Zhao, Zihuan Zhang, Dayong Xia, Jiaqiang Liu, Jiajia Yu, Liying Hu, Yuchen Wang, Zhenbao Li, Niansheng Lai.

   BACKGROUND: Ferroptosis in pathophysiological mechanisms in early brain injury after subarachnoid hemorrhage (SAH-EBI) has been demonstrated. MicroRNAs (miRNAs) are involved in various aspects of neurological disorders. A growing number of studies suggest that intense inflammation mediated by M1 microglia after subarachnoid hemorrhage (SAH) may lead to neurological damage. According to our research and related reports, exosomal miR-369-3p is involved in the pathophysiological process of SAH, and miR-369-3p has a potentially central role in regulating inflammatory responses. Therefore, targeted delivery of miR-369-3p across the blood-brain barrier (BBB) into the brain to alleviate SAH-EBI is a promising therapeutic approach.
METHODS: In this study, we extracted exosomes from RBCs and then modified RVG peptide onto the exosome surface using the click chemistry principle. Finally, miR-369-3p mimic was loaded into the RVG peptide-modified exosomes to form RVG-Exo/miR-369-3p (RVG-Exo/miR) by electroporation. Tail vein injection of RVG-Exo/miR was used to achieve delivery of miR-369-3p into the brain of SAH mice. The effect of miR-369-3p on SAH-EBI was examined by neurobehavioral scores, brain water content, Fluoro-Jade C (FJC) staining, and Nissl staining. MDA and GSH kits were used to assess the extent of ferroptosis occurrence. Western blotting analysis, immunofluorescence staining, and qRT-PCR were used to detect the levels of each protein, mRNA, and miRNA.
RESULTS: The exosome system (RVG-Exo/miR) successfully delivered miR-369-3p to the mouse central nervous system across the blood-brain barrierBBB. This exosomal system reduced the number of M1 microglia by enhancing their sensitivity to ferroptosis by inhibiting the expression of iNOS and GPX4. In addition, miR-369-3p treatment alleviated neurobehavioral disorders, brain edema, and neuronal damage after SAH-EBI.
CONCLUSIONS: RVG-Exo/miR promotes ferroptosis in M1 microglia by inhibiting the iNOS/GPX4 axis, which may be a new and effective therapeutic strategy for treating SAH-EBI.

Keywords:  exosomes; ferroptosis; microRNA‐369‐3p; subarachnoid hemorrhage

DOI:  https://doi.org/10.1002/brb3.70966
Brain. 2025 Oct 16. pii: awaf372. [Epub ahead of print]

PET-MRI biomarkers reveal efficacy of a novel NLRP3 inhibitor in Parkinson's disease models.

Eduardo A Albornoz, Karine Mardon, Rajiv Bhalla, Vinod Kumar, Damion H R Stimson, Gary Cowin, Cedric S Cui, Mark S Butler, Ruby Pelingon, Richard Gordon, Rebecca C Coll, Kate Schroder, Reena Halai, Angus M MacLeod, Kim Matthews, Avril A B Robertson, Matthew A Cooper, Trent M Woodruff.

  Parkinson's disease is one of the fastest-growing neurodegenerative disorders, with no effective treatments to modify its progression. Microglial-driven neuroinflammation, mediated by NLRP3 inflammasome activation, plays a key role in disease onset and progression. The NLRP3 inflammasome is upregulated in microglia from Parkinson's disease patients and activated by oxidative stress and a-synuclein aggregates, triggering the release of pro-inflammatory mediators that contribute to neuroinflammation and neuronal death. MCC950, the first described specific NLRP3 inhibitor, has shown promise in Parkinson's disease models but is limited by suboptimal pharmacokinetics and safety, hindering its clinical development. Here, we developed a novel NLRP3 inflammasome inhibitor, MCC7840 (also known as Inzomelid or Emlenoflast), and utilised clinically relevant PET-MRI imaging biomarkers to assess its therapeutic efficacy in preclinical models of Parkinson's disease. MCC7840 inhibited NLRP3 in human and mouse microglia with nanomolar potency, while demonstrating improved systemic exposure, half-life, brain permeability, and bioavailability compared to MCC950. In a murine NLRP3 gain-of-function model of Muckle-Wells syndrome, MCC7840 effectively inhibited mortality and demonstrated superior potency compared to MCC950. Chronic oral administration of MCC7840 protected against neuroinflammation, motor deficits, and dopamine loss in both 6-hydroxydopamine and preformed α-synuclein fibril mouse models of Parkinson's disease. Radiotracer imaging of multiple PET markers in the same mouse revealed that MCC7840 attenuated neuroinflammation ([18F]DPA-714), preserved dopamine uptake ([18F]FDOPA), mitigated dopamine transporter loss ([18F]FBCTT), and reduced blood-brain barrier leakage (gadolinium contrast MRI). Notably, MCC7840 was effective in a slowly progressing 12-month α-synuclein model, even when administered after symptom onset, 4 months post-α-synuclein injection. These findings highlight the utility of PET/MRI as a non-invasive tool to evaluate drug efficacy and support MCC7840, and other brain-penetrant NLRP3 inhibitors, as promising disease-modifying therapies for Parkinson's disease, warranting future clinical investigation.

Keywords:  PET imaging; Parkinson’s disease; drug discovery; inflammasome; neuroinflammation

DOI:  https://doi.org/10.1093/brain/awaf372
J Stroke Cerebrovasc Dis. 2025 Oct 10. pii: S1052-3057(25)00246-0. [Epub ahead of print]34(12): 108469

VU0360172 exerts anti-inflammatory effect on germinal matrix hemorrhage in neonatal rats via the mGluR5/PI3Kγ/PPARγ pathway.

Xiaoya Wang, Jianwei Xu, Ying Liu, Qin Chen, Rongjie Liu, Qing Zhang, Ying Xiong, Zhanhui Feng, Qian Zheng, Lan Ye.

   BACKGROUND: This study investigated the neuroprotective and anti-inflammatory effects of the mGluR5-specific positive allosteric modulator VU0360172 on germinal matrix hemorrhage (GMH) in neonatal rats, as well as the pharmacological mechanism pathway that may underlie this anti-inflammatory effect.
METHODS: A GMH model was established by intracerebral injection of 0.3 U collagenase VII-S in 7-day-old Sprague-Dawley rats. Animals were randomly divided into the following seven groups: (1) Sham, (2) GMH, (3) GMH +VU0360712 (0.75 mg/kg), (4) GMH + VU0360712 (1.5 mg/kg), (5) GMH + VU0360712 (3.0 mg/kg), (6) GMH + VU0360172 (3.0 mg/kg) + MTEP (0.6 mg/kg), and (7) GMH + VU0360172 (3.0 mg/kg) + AS-605240 (1.8 mg/kg). Western blot analysis was conducted on samples collected at 0, 3, 12 and 24 h and 3 and 7 days post-surgery to observe the postoperative changes in metabotropic glutamate receptor 5 (mGluR5). The neuroprotective and anti-inflammatory effects of different doses of VU0360172 (0.75, 1.5, and 3.0 mg/kg) on GMH were evaluated through neurological behavior testing, brain water content, brain hemorrhage volume, hematoxylin and eosin staining, and ELISA. Finally, MTEP and AS-605240 as inhibitors, were administered to explore the inflammatory regulation and microglial polarization regulation of the mGluR5/PI3Kγ/PPARγ pathway.
RESULTS: The results demonstrated that mGluR5 levels started to decline as early as 3 hours after GMH and reached a minimum at 24 hours. Compared with the GMH group, treatment with VU0360172 reduced improved neurological deficits, brain edema, and hemorrhage, reduced tissue loss and inflammatory cell infiltration, and alleviated the inflammatory response, with the middle and high doses showing particularly notable effects (P < 0.05). However, both MTEP and AS-605240 reversed the regulatory effects of VU0360172 on the mGluR5/PI3Kγ/PPARγ pathway. Significant reversals in the expression of key inflammatory factors and microglial markers were observed in the MTEP and AS-605240 groups compared to the high-dose VU0360172 group (P < 0.05).
CONCLUSION: VU3060172 has a neuroprotective effect and anti-inflammatory properties on the GMH mouse model. Its anti-inflammatory mechanism may be achieved by activating the mGluR5/PI3Kγ/PPARγ pathway to regulate microglial polarization.

Keywords:  Germinal matrix hemorrhage; Metabotropic Glutamate Receptor 5; PI3K gamma protein; PPAR gamma; VU0360172; anti-inflammation; microglia

DOI:  https://doi.org/10.1016/j.jstrokecerebrovasdis.2025.108469
Aging Cell. 2025 Oct 13. e70259

Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Cognitive Decline by Restoring Senescent Microglial Function via NF-κB-SREBP1 Pathway Inhibition.

Aihong Liang, Li Zhang, Jing Peng, Yanan Li, Yunduo Zhou, Chao Yang, Jie Wang, Yizhong Yan, Hua Mei, Jun Zhu, Siqi Wang, Na Xiao, Yu Zhou, Lamei Cheng.

  Aging is a major risk factor for neurodegenerative diseases, yet the role of senescent microglia in age-related cognitive dysfunction remains incompletely understood. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been extensively studied for their significant potential in anti-aging. In this study, we demonstrated that hUC-MSCs ameliorate age-related cognitive decline and downregulate senescence-associated markers in the aged hippocampus. Furthermore, co-culture experiments showed that senescent microglia exacerbate neuronal senescence and neuroinflammation, while also suppressing the apoptosis of senescent neurons. These findings suggested that senescent microglia contribute to age-related cognitive decline by exacerbating neuronal damage and impairing senescent neurons' clearance. We also elucidated a novel mechanism by which hUC-MSCs alleviate age-related cognitive decline by targeting senescent microglia. Specifically, we showed that hUC-MSCs reduce senescence-associated markers, decrease lipid droplet accumulation, and restore phagocytic function in senescent microglia through the inhibition of the NF-κB-SREBP1 pathway. This pathway modulation attenuates neuronal damage and promotes the apoptosis of senescent neurons, facilitating the clearance of damaged neurons. These findings highlight the therapeutic potential of hUC-MSCs in age-related neurodegenerative disorders.

Keywords:  aging; hUC‐MSCs; lipid droplets; microglia; neuron

DOI:  https://doi.org/10.1111/acel.70259
Front Immunol. 2025 ;16 1667097

Pro-inflammatory S100A9 contributes to retinal ganglion cell degeneration in glaucoma.

Zuo Wang, Yang Chen, Jinxia Wang, Wenbo Xiu, Gao Zhang, Yanping Gao, An Li, Ping Long, Bolin Deng, Chong He, Fang Lu.

  S100A9 is a pro-inflammatory protein involved in neuroinflammation and central nervous system (CNS) neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Glaucoma, the leading cause of irreversible blindness, shares common pathogenic mechanisms with CNS disorders. These parallels suggest a potential role for S100A9 in glaucoma; however, its precise contribution remains unclear. In this study, we investigated the association between S100A9 and glaucoma by enrolling 121 patients with glaucoma, administering intravitreal injections of recombinant murine S100A9 (rmS100A9), and employing an elevated intraocular pressure (EIOP)-induced glaucoma mouse model. We found that circulating S100A9 levels were elevated in patients with glaucoma and positively associated with disease stage. Retinal S100A9 expression was significantly elevated and correlated with progressive retinal ganglion cell (RGC) loss in EIOP glaucoma mice. Furthermore, intravitreal injection of rmS100A9 led to direct RGC degeneration. Both enrichment analyses and experimental validation indicated that S100A9 may contribute to glaucomatous injury by promoting neuroinflammatory responses in retinal microglia and astrocyte via activation of the Toll-like receptor 4 (TLR4) pathway. These results raise the possibility that S100A9 as a potential target for future therapeutic exploration in glaucoma.

Keywords:  S100A9; glaucoma; glial activation; neuroinflammation; retinal neurodegeneration

DOI:  https://doi.org/10.3389/fimmu.2025.1667097
Front Immunol. 2025 ;16 1657524

Akkermansia muciniphila alleviates cognitive impairment and neuroinflammation induced by blunt chest trauma.

Lin Liu, Linxiao Wang, Yanjun Wang, Heping Zhao, Xi Gao, Wen Yin, Jiangang Xie.

   Background: Blunt chest trauma, commonly caused by traffic accidents, falls, and violent incidents, results in both direct mechanical injury to the thoracic cavity-leading to increased intrathoracic pressure and vascular rupture-and indirect effects on the central nervous system (CNS), causing extensive damage that severely impacts patient health and quality of life. Akkermansia muciniphila (AKK), a probiotic bacterium inhabiting the gut mucus layer, modulates gut microbiota and metabolites, with potential therapeutic effects on various neurological disorders through the gut-brain axis.
Methods: Mice were divided into four groups: control, trauma, trauma+PBS, and trauma+AKK. AKK bacterial suspension was administered via gavage for three weeks. Behavioral tests including the OFT, EPM, NORT, and Y-maze were conducted to assess anxiety-like behaviors and cognitive function. Neuroinflammatory markers in the hippocampus were measured using qPCR, immunofluorescence, and Western blot. Gut microbiota and metabolites were analyzed through 16S rRNA sequencing and metabolomics.
Results: Mice subjected to blunt chest trauma displayed emotional abnormalities and cognitive deficits. AKK treatment significantly alleviated anxiety-like behaviors and improved cognitive function, reduced pro-inflammatory cytokine levels in the hippocampus, and reshaped gut microbiota composition. AKK also modulated the expression of metabolites linked to neuroinflammation and cognitive function, upregulated BDNF and TrkB, and decreased IBA1, suggesting it enhances cognitive function by modulating neuroinflammation and the BDNF/TrkB signaling pathway.
Conclusions: AKK mitigates cognitive impairment and neuroinflammation after blunt chest trauma by modulating gut microbiota and metabolites. Targeting the gut-brain axis may offer new strategies for preventing and treating trauma-induced neurological disorders.

Keywords:  Akkermansia muciniphila; BDNF; blunt chest trauma; cognitive function; microglia; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2025.1657524
Acta Neuropathol Commun. 2025 Oct 13. 13(1): 214

Ablation of progranulin augments microglial activation and accelerates prion progression.

Bei Li, Yiyue Shi, Wenyu Hou, Haoyuan Guan, Jun Li, Tuo Yi, Wei Li, Donglin Cai, Petra Schwarz, Adriano Aguzzi, Caihong Zhu.

  Mutations or polymorphisms in GRN, encoding the CNS glycoprotein progranulin (PGRN), have been linked to several neurodegenerative diseases. In this study, we explored the role of PGRN in prion diseases. We observed that prion infection upregulated microglial PGRN expression. Following intracerebral inoculation with RML6 prions, Grn-/- mice exhibited accelerated disease progression compared to Grn+/- and Grn+/+ littermates. Histological analysis revealed augmented microglial activation in Grn-/- mice. Temporal analysis revealed enhanced early microglial activation and prion clearance at 120 dpi, followed by excessive complement activation but inadequate clearance by 150 dpi. Additionally, Grn-/- brains exhibited exacerbated astrogliosis and vacuolation. RNA-seq analysis indicated that complete PGRN deficiency in prion-infected mice shifted microglia from homeostatic to pro-inflammatory states. Notably, microglia-specific depletion of PGRN did not affect prion pathogenesis, suggesting that PGRN deficiency affects microglial activation and prion progression in a non-cell autonomous manner. These findings suggest that microglia respond to prion infection in a stepwise manner, and PGRN plays a critical role in modulating prion-induced microglial activation. Our results highlight the neuroprotective role of PGRN in prion disease and suggest that supplementation or boosting expression of PGRN could represent a promising therapeutic strategy.

Keywords:  Microglia; Neurodegeneration; Neuroinflammation; Prion disease; Progranulin

DOI:  https://doi.org/10.1186/s40478-025-02128-3
Life Sci. 2025 Oct 14. pii: S0024-3205(25)00659-9. [Epub ahead of print] 124023

Circulating plasma exosomal miR-146b-5p regulates microglial-mediated neuroinflammation through the TRAF6/NF-κB signaling axis after intracerebral hemorrhage.

Fuan Zhang, Chong Han, Jiao Chen, Ziqiang Chen, Ning Ding, Xuyang Zhang, Fengchun Zhao, Lanying Zhang, Peirui Wang, Fang Cao, Rong Hu, Shengtao Yao.

   AIMS: The effect of miR-146b-5p on microglial polarization and neuroinflammation post-intracerebral hemorrhage (ICH) remains unclear. We investigated the role of circulating plasma exosomal miR-146b-5p in microglial polarization and neuroinflammation following ICH.
MATERIALS AND METHODS: Plasma was isolated from peripheral blood collected from ICH patients and healthy individuals. Bioinformatic analysis identified differentially expressed miRNAs and their target genes. The interaction between miR-146b-5p and its target genes was confirmed using a dual-luciferase reporter assay. Using lipopolysaccharide (LPS)-induced microglial inflammation and ICH mouse models, we assessed the role of miR-146b-5p in microglial polarization and neuroinflammation. miR-146b-5p's regulatory influence on the tumor necrosis factor receptor-associated factor 6/nuclear factor kappa B (TRAF6/NF-κB) pathway was confirmed using knockdown and overexpression experiments of TRAF6.
KEY FINDINGS: The plasma exosome levels of miR-146b-5p in ICH were markedly reduced compared to those in healthy controls. miR-146b-5p overexpression facilitated M2 polarization of microglia and decreased TNF-α, interleukin-1β (IL-1β), and IL-6 levels. Conversely, inhibition of miR-146b-5p had the opposite effect. A dual-luciferase assay indicated that TRAF6 was directly targeted by miR-146b-5p. TRAF6 knockdown inhibited NF-κB activation and enhanced M2 polarization. However, TRAF6 overexpression reversed these effects. Rescue experiments demonstrated that TRAF6 knockdown reversed the phenotypic effects of the miR-146b-5p inhibitor.
SIGNIFICANCE: Circulating plasma exosomal miR-146b-5p modulates microglial polarization and neuroinflammation via the TRAF6/NF-κB signaling pathway following ICH, providing neuroprotective benefits. These findings may contribute to the development of innovative therapeutic approaches.

Keywords:  Intracerebral hemorrhage; Microglia; Neuroinflammation; TRAF6; miR-146b-5p

DOI:  https://doi.org/10.1016/j.lfs.2025.124023
Mol Neurodegener. 2025 Oct 17. 20(1): 109

Synaptic dysfunction and glial activation markers throughout aging and early neurodegeneration: a longitudinal CSF biomarker-based study.

Mariana I Muñoz-García, Yuetiva Deming, Ferran Lugo-Hernández, Sterling Johnson, Sanjay Asthana, Gwendlyn Kollmorgen, Clara Quijano-Rubio, Cynthia Carlsson, Ozioma C Okonkwo, David Pérez-Martinez, Alberto Villarejo-Galende, Kaj Blennow, Marc Suárez-Calvet, Henrik Zetterberg, Barbara B Bendlin, Estrella Morenas-Rodríguez.

   BACKGROUND: Synaptic homeostasis, maintained by microglia and astroglia, is disrupted throughout aging and early on in neurodegenerative diseases. Our aim was to study the relationship between TREM2-dependent microglial reactivity, astroglial response and synaptic dysfunction in two longitudinal cohorts of cognitively healthy volunteers and determine whether this relationship is influenced by AD core biomarkers.
METHODS: We analyzed cross-sectional and longitudinal associations between cerebrospinal fluid levels of soluble TREM2 (sTREM2), astroglial markers (GFAP, S100B), and synaptic markers (neurogranin, α-synuclein) in cognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP) and the Alzheimer's and Families (ALFA+) cohort. Biomarkers were quantified using validated immunoassays (NeuroToolKit, Roche), with sTREM2 measured using an in-house MSD-based assay in the WRAP cohort. Linear regression and linear mixed-effects models were used, both unadjusted and adjusted for Aβ42 and p-tau. Subgroup analyses were performed based on AT classification, APOE-ε4 status, and median splits of Aβ42/Aβ40 ratio and p-tau, to capture profiles suggestive of early AD-related neuropathogenesis.
RESULTS: We found significant cross-sectional associations between sTREM2 and α-synuclein, as well as between sTREM2 and S100B, in subgroups exhibiting AD-related biomarker profiles. Longitudinally, lower baseline neurogranin and α-synuclein and higher S100B predicted greater increases in sTREM2 over time independently of AD-related markers in the WRAP cohort (β = -0.02, p = 0.006; β = -0.02, p = 0.01; β = 0.02, p = 0.03, respectively). In ALFA+, lower baseline α-synuclein also predicted a greater subsequent longitudinal increase in sTREM2, but only among individuals with Aβ42/Aβ40 ratio above the median (β = -0.01, p = 0.05). Notably, higher baseline sTREM2 was associated with a smaller longitudinal increase in neurogranin in both cohorts (β = -0.01, p = 0.03 for WRAP, β = -0.01, p = 0.04 in ALFA+).
CONCLUSIONS: Synaptic dysfunction markers at baseline influence the longitudinal dynamics of CSF sTREM2 independently of AD-pathology related biomarkers throughout aging and earliest stages of neurodegeneration. In turn, higher baseline sTREM2 is associated with more stable neurogranin levels over time. These results suggest an independent interaction between synaptic dysfunction and TREM2-dependent microglial activation throughout aging and early neurodegeneration beyond AD pathology.

Keywords:  Aging; Microglia; Neurodegeneration; Synaptic function; TREM2

DOI:  https://doi.org/10.1186/s13024-025-00901-5
Sci Rep. 2025 Oct 13. 15(1): 35567

Retinal degeneration driven by brain-derived neurotrophic factor deficiency in microglia and T-lymphocytes.

Sabrina Reinehr, Julia P Zehge, Katharina Klöster, Maike Mueller, Hasan H Hendek, Michael Sendtner, H Burkhard Dick, Ralf Gold, Stephanie C Joachim, Simon Faissner.

  Neurodegenerative diseases, such as glaucoma or multiple sclerosis, are characterized by progressive neuronal loss involving diverse pathogenic mechanisms. The brain-derived neurotrophic factor (BDNF) has been implicated in neuroprotection and neural plasticity, yet its regulation and involvement in retinal neurodegenerative diseases remain largely unclear. In this study, we investigated the impact of BDNF deficiency in immune cells on retinal integrity. Using mice with a conditional BDNF knockout in microglia/macrophages and T-cells or selectively in microglia/macrophages, we analyzed retinal changes at 3 and 7 months of age, with wildtype mice as controls. BDNF-deficient mice exhibited early and progressive degeneration of retinal ganglion cells and photoreceptors, accompanied by pronounced astrogliosis, which was exacerbated in aged animals. In 7-month-old mice, adaptive changes in synapses could be documented, evidenced through enhanced expression of the vesicular acetylcholine transporter. These findings demonstrate that BDNF from immune cells plays a crucial role in maintaining retinal homeostasis and that its loss promotes retinal neurodegeneration. Targeting immune cell-derived BDNF may offer novel therapeutic strategies for retinal involvement in neurodegenerative diseases with implications for treatment of glaucoma or multiple sclerosis.

Keywords:  Astrogliosis; Brain-derived neurotrophic factor; Glaucoma; Microglia; Multiple sclerosis; Neurodegeneration; Retinal ganglion cells

DOI:  https://doi.org/10.1038/s41598-025-21423-6
Commun Biol. 2025 Oct 16. 8(1): 1475

OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies.

Qinglong Wang, Yiqi Wang, Yi Da Douglas Jiang, Ryan Donahue, Gaby Cao, Weixuan Yan, Hong Guo, Zhenghui Li, Jenna Liang, Jin Hao, Yi Lu, Fengfeng Bei, Qianbin Wang, Feng Tian.

Optineurin (OPTN) is an adaptor protein that plays a crucial role in many cellular pathways, including NF-κB signaling, programmed cell death, and vesicular trafficking. OPTN dysfunction has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS). While mutations of OPTN seem to be predominantly loss-of-function in ALS, only gain-of-function mechanisms have been reported in POAG. Here, we demonstrate that OPTN knockout in the retina contributes to short-term astrogliosis, retinal ganglion cell (RGC) loss and long-term microglial activation. Moreover, OPTN loss of function does not exacerbate RGC death induced by ocular hypertension. Integrated bioinformatics and immunofluorescence analyses reveal that OPTN dysfunction leads to neuropeptide Y (NPY) downregulation and CHOP upregulation. Overexpression of wild-type OPTN in a hypertension glaucoma model prevents the RGC loss and attenuates microglial activation. Together, our findings highlight a neuroprotective role for OPTN as a key neuroimmune modulator.

DOI: https://doi.org/10.1038/s42003-025-08534-6
Curr Med Chem. 2025 Oct 08.

Neuroinflammatory Human Brain Organoids Enable Comprehensive Drug Screening Studies: Fingolimod and its Analogues in Focus.

Busra Acar, Nihan Aktas Pepe, Aleksandra Zivkovic, Holger Stark, Alaattin Sen.

   INTRODUCTION: The absence of physiologically relevant models for neuroinflammatory brain disorders, such as multiple sclerosis (MS), highlights the need for improved drug screening platforms. To bridge this gap, this study aimed to develop a human brain organoid (hBO) model incorporating essential neural cell types, including astrocytes, microglia, and oligodendrocytes.
METHODS: hBOs were generated from H9 stem cells, and neuroinflammatory characteristics were elicited by lipopolysaccharide (LPS). The expression of specific neuronal and inflammatory markers was assessed through qRT-PCR, immunofluorescence staining (IFS), and ELISA.
RESULTS: IFS of mature hBOs with anti-SOX2, anti-SATB2, anti-MAPT, anti-GFAP, anti- MBP, and anti-IBA1 antibodies and images collected with the confocal microscope confirmed the differentiation of H9 cells into cortical neurons, astrocytes, microglia, and oligodendrocyte cell types. Elevated GFAP, IBA1, NF-κB, and IL-6 levels, along with reduced CNPase expression with LPS treatment, were considered reflective of MS-like pathology and were used to test fingolimod and its derivatives. Fingolimod and all its derivatives, specifically ST-1505, decreased MAPT (2.1-fold in ELISA, 1.7-fold in IFS), GFAP (1.8-fold in IFS), TNFα (5.4-fold in qRT-PCR), and FABP (1.5-fold in ELISA) levels, and increased IL-10 (11-fold in qRT-PCR) and MBP (2.9-fold in IFS) levels.
DISCUSSION: The present data collectively showed LPS to evoke neuroinflammation in the hBO model, while fingolimod and its derivatives, particularly ST-1505, exhibited significant anti-inflammatory and neuroprotective properties by counteracting these evoked changes in the hBO model.
CONCLUSION: The findings supported the applicability of brain organoids as a model system for drug screening studies for neuroinflammatory brain diseases.

Keywords:  Brain organoid; drug screening; fingolimod; fingolimod derivatives.; multiple sclerosis

DOI:  https://doi.org/10.2174/0109298673435364251002112630