bims-microg 2025-12-07 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–12–07
fifteen papers selected by
Marcus Karlstetter, Universität zu Köln

IL-17A-mediated copper accumulation participates in chronic neuropathic pain-induced cognitive impairment by enhancing microglial synaptic pruning.
Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease.
Bi-directional communication between regulatory T cells and microglia promotes recovery from spinal cord injury.
Retinal Pigment Epithelium Extracellular Vesicles Induce Microglia Polarization in MERTK-Associated Retinal Degeneration.
DAP12 deletion reduces neuronal SLIT2 and demyelination and enhances brain resilience in female tauopathy mice.
SIK2 mediated mitochondrial homeostasis in spinal cord injury: modulating oxidative stress and the AIM2 inflammasome via CRTC1/CREB signaling.
Extracellular microRNAs modulate human microglial function through TLR8.
Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia.
High throughput identification of genetic regulators of microglial inflammatory processes in Alzheimer's disease.
Differential microglial responses to structurally distinct alpha-synuclein polymorphs.
Human oligodendrocyte progenitor cells mediate synapse elimination through TAM receptor activation.
Calcaratarin D exerts neuroprotective effects in Alzheimer's disease mouse model by inhibiting CERT-mediated NF-κB pathway.
Neuronal alpha-synuclein-mediated autophagy drives lipid droplets accumulation in astrocytes and microglia and aggravates ischemic stroke.
Human neural stem cell-derived exosomes promote functional recovery in subarachnoid hemorrhage via bdnf/trkb pathway activation and astrocyte modulation.
Extracellular vesicle-derived miR21 of non-tumoral origin as early diagnostic marker of glioma.

Brain Behav Immun. 2025 Dec 03. pii: S0889-1591(25)00450-7. [Epub ahead of print] 106208

IL-17A-mediated copper accumulation participates in chronic neuropathic pain-induced cognitive impairment by enhancing microglial synaptic pruning.

Jie Liu, Zheng Li, Xiaoling Peng, Wei Zhao, Tiantian Chu, Jie Ju, Jihao Ren, Feng Gao.

  Chronic neuropathic pain is frequently accompanied by cognitive impairment, which seriously influence the quality of the patient's life. The stability of synapse is the basis for maintaining neural circuits. And overactive microglia can prune normal synapses through phagocytosis, leading to cognitive impairment. This study aims to investigate the role of microglial synaptic pruning in chronic neuropathic pain-induced cognitive impairment, and explore the mechanisms of microglial activation through Interleukin-17A (IL-17A) activation and copper accumulation. We found that chronic neuropathic pain resulted in cognitive impairment, and microglial activation, abnormal microglial synaptic pruning, synaptic loss in hippocampus. Depleting microglia ameliorated the activations of microglial and complement pathways, and rescued synaptic loss and cognitive impairment. The copper was accumulated in hippocampus, and copper chelator tetrathiomolybdate (TTM) inhibited microglial and complement activations and rescued synaptic loss and cognitive impairment. Further research found that suppressing mitochondrial oxidative stress response inhibited copper accumulation-induced microglial activation. Finally, IL-17A was found to be increased in serum and hippocampus. IL-17A neutralization antibody (anti-IL-17A Abs) alleviated copper accumulation by inhibiting six transmembrane epithelial antigens of prostate 4 (STEAP4) / copper transporter 1 (CTR1), and inhibited microglial and complement activation, interrupting abnormal synaptic elimination and ameliorating cognitive impairment. Our results suggest that IL-17A can induce copper accumulation in microglia through STEAP4/CTR1, the latter promotes complement-mediated microglia synaptic pruning, reducing synapse number, and ultimately resulting in cognitive impairment. These provide a new potential therapeutic target for the treatment of chronic neuropathic pain-induced cognitive impairment.

Keywords:  Chronic neuropathic pain; Cognitive impairment; Copper accumulation; IL-17A; Microglia; Synaptic pruning

DOI:  https://doi.org/10.1016/j.bbi.2025.106208
Sci Transl Med. 2025 Dec 03. 17(827): eadw7428

Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease.

Tanya N Weerakkody, Hanna Sabelström, Shan V Andrews, Jean Paul Chadarevian, Marcus Y Chin, David Tatarakis, Nicholas E Propson, Do Jin Kim, Richard Theolis, Gian Carlo G Parico, Hiwot Misker, Jennifer E Kung, Abira Bandyopadhyay, Yaneth Robles Colmenares, Taggra-Nicole Jackson, Ahlam N Qerqez, Srijana Balasundar, Sonnet S Davis, Connie Ha, Rajarshi Ghosh, Ritesh Ravi, Anil Rana, Kyla Germain, Arnold Tao, Ken Xiong, Dylan Braun, Karthik Raju, Kang-Chieh Huang, Lihong Zhan, Jing L Guo, Hoda Safari Yazd, Lily Sarrafha, Joia Kai Capocchi, Jonathan Hasselmann, Alina L Chadarevian, Christina Tu, Kimiya Mansour, Ghazaleh Eskandari-Sedighi, Niccolò Tesi, Sven van der Lee, Marc Hulsman, Georgii Oshegov, Yolande Pijnenburg, Meredith Calvert, Henne Holstege, Jung H Suh, Gilbert Di Paolo, Hayk Davtyan, Joseph W Lewcock, Mathew Blurton-Jones, Kathryn M Monroe.

The Alzheimer's disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is an immunoreceptor tyrosine-based inhibitory motif domain-containing inhibitory receptor, expressed by myeloid cells such as microglia. The known protective PILRA G78R gene variant reduces AD risk in apolipoprotein E4 (APOE4) carriers and is enriched in a cohort of healthy centenarians. However, mechanisms underlying protective effects in microglia are undefined. Here, we identified biological functions of PILRA in human induced pluripotent stem cell-derived microglia (iMG) and chimeric AD mice. PILRA knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. PILRA KO also enhanced microglial chemotaxis and attenuated inflammation. With pharmacological inhibitor studies, we showed that peroxisome proliferator-activated receptor and signal transducer and activator of transcription 1/3 mediated PILRA-dependent microglial functions. AD mice transplanted with human PILRA KO microglia exhibited reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand blocking PILRA antibody phenocopied PILRA KO iMG. These findings suggest that PILRA is a pharmacologically tractable therapeutic target for AD.

DOI: https://doi.org/10.1126/scitranslmed.adw7428
Neuron. 2025 Dec 03. pii: S0896-6273(25)00802-5. [Epub ahead of print]113(23): 3877-3879

Bi-directional communication between regulatory T cells and microglia promotes recovery from spinal cord injury.

Jiajing Shan, Xiaoming Hu.

In this issue of Neuron, Qin et al.1 demonstrate that regulatory T cells (Tregs) are essential for tissue preservation and functional recovery after spinal cord injury, highlighting bilateral communication between Tregs and microglia as a key mechanism underlying Treg-mediated protection.

DOI: https://doi.org/10.1016/j.neuron.2025.10.021
Invest Ophthalmol Vis Sci. 2025 Dec 01. 66(15): 1

Retinal Pigment Epithelium Extracellular Vesicles Induce Microglia Polarization in MERTK-Associated Retinal Degeneration.

Hang Zhang, Zhen-Yu Liu, Lingzi Wu, Jing Yuan, Xiao Zhang, Xiao-Hui Zhang, Yang Li, Fei Liu, Zi-Bing Jin.

Purpose: Retinitis pigmentosa (RP) is a hereditary retinal disease. MERTK-associated RP is characterized by earlier onset and rapid progression, featuring retinal pigment epithelium (RPE) inflammation and microglial activation, yet the underlying mechanisms remain incompletely understood. The study aimed to elucidate the intrinsic interactions between RPE inflammation and microglial activation mediated by RPE-derived extracellular vesicles (EVs).
Methods: Induced pluripotent stem cell (iPSC)-derived RPE models from MERTK mutant patients and healthy controls were established and characterized by transcriptomic analysis. RPE-derived EVs were isolated, and their RNA and protein cargo were systematically profiled using transcriptomic and proteomic data, revealing a potential role in retinal inflammation regulation. The effects of RPE-EVs on microglial activation were confirmed through in vitro co-culture and in vivo animal experiments.
Results: Transcriptomic analysis revealed that differentially expressed genes between MERTK mut-RPE (M-RPE) and control RPE (C-RPE) were enriched in inflammatory signaling pathways and EV-related terms. Multi-omics data further indicated that the altered RNA and protein cargo of M-RPE-derived EVs were closely associated with inflammation and immune regulation. In vitro co-culture confirmed that M-EVs could rapidly activate microglia and upregulate pro-inflammatory factors. In vivo experiments indicated that microglia phagocytosed M-EVs exhibited more pronounced M1 polarization and migratory changes.
Conclusions: RPE-derived EVs act as critical drivers of microglial M1 polarization in MERTK-associated RP. Our study revealed their pivotal role in the progression of early-onset severe RP, providing theoretical support for the potential of targeting EVs to modulate the retinal immune microenvironment and intervene in the progression of retinal degeneration.

DOI: https://doi.org/10.1167/iovs.66.15.1
Mol Neurodegener. 2025 Dec 02. 20(1): 124

DAP12 deletion reduces neuronal SLIT2 and demyelination and enhances brain resilience in female tauopathy mice.

Hao Chen, Li Fan, Qi Guo, Man Ying Wong, Jingjie Zhu, Nessa Foxe, Winston Wang, Aviram Nessim, Gillian Carling, Bangyan Liu, Chloe Lopez-Lee, Yige Huang, Sadaf Amin, Tark Patel, Sue-Ann Mok, Won-Min Song, Bin Zhang, Shiaoching Gong, Qin Ma, Hongjun Fu, Li Gan, Wenjie Luo.

   BACKGROUND: Pathogenic tau accumulation drives neurodegeneration in Alzheimer's disease (AD). Enhancing the aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12), highly and selectively expressed by microglia, plays a crucial role in microglial immune responses. Previous studies have shown that tauopathy mice lacking DAP12 exhibit higher tau pathology but are protected from tau pathology-induced cognitive deficits. However, the exact mechanism behind this resilience remains elusive.
METHODS: We investigated the effects of DAP12 deletion on tau pathology, as well as tau-induced brain inflammation and neurodegeneration, in homozygous human Tau P301S transgenic mice. In addition, we conducted single-nucleus RNA sequencing of hippocampal tissues to examine cell type-specific transcriptomic changes at the single-cell level. Furthermore, we utilized the CellChat package to profile cell-cell communication in the mouse brain and investigated how these interactions are affected by tau pathology and Dap12 deletion.
RESULTS: We demonstrated that Dap12 deletion reduced tau processing in primary microglia and increased tau pathology in female tauopathy mice, with minimal effects on males. Despite this, Dap12 deletion markedly reduced brain inflammation, synapse loss, and demyelination, indicating enhanced resilience to tau toxicity. Single-cell transcriptomic profiling revealed that Dap12 deletion blocked tau-induced alterations in microglia, neurons, and oligodendrocytes. CellChat analysis identified aberrant tau-induced SLIT2 signaling from excitatory neurons to oligodendrocytes. Dap12 deletion suppressed Slit2 upregulation and mitigated demyelination, while lentiviral-Slit2 overexpression induced myelin loss in tauopathy mice. Elevated SLIT2 levels were associated with demyelination in tauopathy mouse model and human AD brains. Spatial transcriptomics revealed a spatial correlation of SLIT2 expression and tau pathology in AD brain tissue.
CONCLUSIONS: Our study identifies a novel DAP12-dependent mechanistic link between upregulated Slit2 expression in excitatory neurons and oligodendrocyte-dependent myelination loss in tauopathy. Despite elevating tau load, the absence of microglial Dap12 ameliorates neuroinflammation and improves brain functions in tauopathy mice. Our study suggests that selectively targeting the toxic aspects of DAP12 signaling while preserving its beneficial functions may be a promising strategy to enhance brain resilience in AD.

Keywords:  Brain resilience; DAP12; Demyelination; SLIT2; Tau toxicity, oligodendrocytes

DOI:  https://doi.org/10.1186/s13024-025-00903-3
J Neuroinflammation. 2025 Dec 03. 22(1): 283

SIK2 mediated mitochondrial homeostasis in spinal cord injury: modulating oxidative stress and the AIM2 inflammasome via CRTC1/CREB signaling.

Nongtao Fang, Yongli Wang, Yige Chen, Yikang Wang, Jiawei Xu, Yangyi Xie, Xiangji Xia, Yaosen Wu, Xiangyang Wang, Yao Li.



Keywords:  Absent in melanoma 2; Microglia; Mitochondria; Salt-inducible kinase 2; Spinal cord injury

DOI:  https://doi.org/10.1186/s12974-025-03606-0
Front Immunol. 2025 ;16 1645062

Extracellular microRNAs modulate human microglial function through TLR8.

Hannah Weidling, Edyta Motta, Leonard D Kuhrt, Christina Krüger, Caio Andreeta Figueiredo, Thomas Wallach, Silke Frahm, Sebastian Diecke, Susanne A Wolf, Helmut Kettenmann, Seija Lehnardt.

   Objective: MicroRNAs (miRNAs) are abundantly expressed in the brain and are specifically dysregulated in central nervous system (CNS) diseases. They act as post-transcriptional gene regulators but can also serve as ligands for Toll-like receptors (TLRs). This study aims to investigate CNS disease-associated miRNAs as signaling molecules for human microglia.
Methods: Using a machine learning algorithm and the disease-linked database PhenoMiR, we identified Alzheimer's disease (AD)- and glioma-associated miRNAs as ligands for TLR7 and TLR8. Expression of human TLR7 and TLR8 in iPSC-derived human microglia-like cells (iMGLs) was validated by RT-qPCR. Using ELISA, scratch assay, and FACS, we investigated the miRNAs' potential to modulate iMGL function, including cytokine release, motility, and phagocytosis, respectively. The selective human TLR8 antagonist CU-CPT9a was used to determine the role of this receptor in miRNA-induced modulation of human microglial activity. Co-cultures of iMGLs and iPSC-derived human cortical neurons (iNeurons) were analyzed by Neurotrack imaging to assess the effects of miRNAs on human neurites.
Results: We identified AD- and glioma-associated miR-9-5p, miR-132-5p, miR-340-3p, miR-30e-3p, miR-501-3p, and let-7b as ligands for human TLR7 and TLR8. Exposure of iMGLs to select miRNAs, including miR-9-5p, miR-132-5p, and miR-340-3p, led to interleukin-6 (IL-6) and tumor necrosis factor (TNF) mRNA expression and protein release in a sequence-dependent fashion. Also, these miRNAs acting as signaling molecules, modulated iMGL motility and phagocytosis activity. The miRNA-induced effects on iMGLs were abolished by CU-CPT9a. Extracellular delivery of miR-132-5p and miR-9-5p to co-cultures of iNeurons and iMGLs resulted in reduced neurite length.
Discussion: Our data establish that distinct CNS disease-associated miRNAs serve as signaling molecules for human microglia via TLR8, thereby controlling the diverse microglial functions and modulating the neuroinflammatory response.

Keywords:  Alzheimer's disease; extracellular microRNA; glioma; human microglia; iPSC; microglial function; stem cells; toll-like receptor 8

DOI:  https://doi.org/10.3389/fimmu.2025.1645062
Nat Commun. 2025 Nov 29.

Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia.

Carla Pernaci, Avalon Johnson, Sydney Gillette, Anna S Warden, Chad McCormick, Sammy Weiser-Novak, Gabriela Ramirez, Emily H Broersma, Priyanka Mishra, Anusha Sivakumar, Stephanie Cherqui, Nicole G Coufal.

Friedreich's ataxia (FRDA) is an incurable neurodegenerative disorder caused by a GAA repeat expansion in the frataxin (FXN) gene, leading to a severe reduction of the mitochondrial FXN protein, crucial for iron metabolism. While microglial inflammation is observed in FRDA, it remains unclear whether immune dysfunction is a primary disease mediator or a secondary reactionary phenotype. Utilizing patient-derived induced pluripotent stem cells (iPSCs), we report an intrinsic microglial phenotype of stark mitochondrial defects, iron overload, lipid peroxidation, and lysosomal abnormalities. These factors drive a pro-inflammatory state that contributes to neuronal death in co-culture systems. In a murine xenograft model, transplanted human FRDA microglia accumulate in white matter and the Purkinje cell layer, resulting in Purkinje neuron loss in otherwise healthy brains. Notably, CRISPR/Cas9-mediated correction of the GAA repeat reverses microglial defects and mitigates neurodegeneration. Here, we suggest that microglial dysfunction serve as a disease driver and a promising therapeutic target in FRDA.

DOI: https://doi.org/10.1038/s41467-025-66710-y
J Neuroinflammation. 2025 Dec 03.

High throughput identification of genetic regulators of microglial inflammatory processes in Alzheimer's disease.

Christopher L Cardona, Lai Wei, Joonwon Kim, Ellen Angeles, Gunjandeep Singh, Shiye Chen, Ronak Patel, Nkechime Ifediora, Peter Canoll, Andrew F Teich, Gunnar Hargus, Alejandro Chavez, Andrew A Sproul.



Keywords:  Alzheimer’s disease; CRISPRi screen; CROP-seq; EED; INPP5D; Inflammation; MS4A6A; Microglia; RABEP1; hiPSCs

DOI:  https://doi.org/10.1186/s12974-025-03562-9
Mol Brain. 2025 Dec 05.

Differential microglial responses to structurally distinct alpha-synuclein polymorphs.

Katherine Chang, Jina Kim, Michiyo Iba, Jae-Hyeon Park, Alexandria Beilina, Zulfeqhar A Syed, Valentina Baena, Liam Horan-Portelance, Mark R Cookson, Sungyong You, Changyoun Kim.

Synucleinopathies are age-related neurological disorders which include dementia with Lewy bodies (DLB), Parkinson's disease (PD), and multiple system atrophy (MSA). A hallmark of these diseases is the pathological accumulation of α-synuclein aggregates, along with sustained neuroinflammatory responses. Recent studies have demonstrated the existence of structurally distinct α-synuclein aggregates in this group of the diseases. While the correlation between specific forms of α-synuclein and distinct pathological characteristics has been extensively studied, their relationship to neuroinflammation remains elusive. Here, we examined the effects of structurally distinct α-synuclein polymorphs on microglial neuroinflammation. Human induced pluripotent stem cells (iPSCs)-derived microglia (iMicroglia, iMG) were treated with α-synuclein polymorphs including EGCG stabilized α-synuclein oligomers (EO), kinetically stable α-synuclein oligomers (KSO), dopamine stabilized α-synuclein oligomers (DO), α-synuclein preformed fibrils (PFF), sonicated α-synuclein preformed fibrils (sPFF), and matured α-synuclein fibrils (Fib). Microglial gene expressions were accessed by transcriptome analysis and Toll-like receptor agonist activities were determined by HEK-Blue TLR reporter assay. Exposures to kinetically stable α-synuclein oligomers and matured α-synuclein fibrils induced the expression of microglial cytokines and chemokines, while other species did not. Microglial transcriptome analysis yielded that all polymorphs commonly induce toll-like receptor (TLR) signaling cascade despite differential transcriptomic phenotypes. Among structurally distinct α-synuclein polymorphs, live cell TLR reporter assay showed that kinetically stable α-synuclein oligomers induce the activities of TLR2 and 4, and sonicated α-synuclein preformed fibril TLR4, relative to the control. These results suggest that structurally distinct α-synuclein polymorphs have likewise distinct neuroinflammatory properties.

DOI: https://doi.org/10.1186/s13041-025-01256-0
Nat Commun. 2025 Dec 05. 16(1): 10612

Human oligodendrocyte progenitor cells mediate synapse elimination through TAM receptor activation.

Asimenia Gkogka, Susmita Malwade, Marja Koskuvi, Sohvi Ohtonen, Ellinor Molnar, Raj Bose, Sandra Ceccatelli, Jari Koistinaho, Jari Tiihonen, Martin Schalling, Samudyata Samudyata, Carl M Sellgren.

Oligodendrocyte progenitor cells (OPCs) have been implicated in synaptic remodelling in animal models, but the underlying mechanisms and their relevance to human brain development remain unclear. Here, we generate a human multi-lineage forebrain organoid model in which OPCs, together with microglia, form close contacts with synapses and spontaneously internalize synaptic material. Single-nucleus transcriptomic profiling with unbiased cell-cell communication analysis identifies the growth arrest-specific gene 6 (GAS6)-TYRO3, AXL, and MERTK (TAM) receptor axis as a key signalling pathway, with neurons and microglia expressing GAS6 and a subset of OPCs expressing AXL. Further, dose-dependent pharmacological inhibition of TAM receptors demonstrates the importance of AXL, and targeted reduction of AXL expression in OPCs impairs synaptic uptake. These findings reveal a role for GAS6-AXL signalling in driving synaptic internalisation by AXL+ OPCs during early human brain development.

DOI: https://doi.org/10.1038/s41467-025-66521-1
Exp Neurol. 2025 Dec 02. pii: S0014-4886(25)00450-9. [Epub ahead of print] 115585

Calcaratarin D exerts neuroprotective effects in Alzheimer's disease mouse model by inhibiting CERT-mediated NF-κB pathway.

Jin-Zhi Pan, Meng-Yao Yu, Ming-Zhu Tian, Run Liu, Wei Zhao, Qian Luo.

  Alzheimer's disease (AD) is a neurodegenerative disease characterized by β-amyloid plaque accumulation, neuroinflammation, and dysregulation of sphingolipid metabolism, mainly manifested as irreversible cognitive decline and memory loss. A key pathological hallmark of AD is neuroinflammation, largely fueled by the persistent stimulation of microglia and subsequent pro-inflammatory cytokine production, which worsens disease development. Calcaratarin D (CalD), a ladanane-type diterpenoid sourced from Hedychium flavum rhizomes, has been reported to exhibit significant anti-inflammatory effects. However, its potential therapeutic benefits in AD remain unknown. Therefore, this research focused on exploring the neuroprotective effects of CalD in AD and elucidating its potential mechanisms. We established a mouse model of AD by targeting delivery of Aβ₁₋₄₂ oligomers to the hippocampus. Behavioral tests showed that CalD significantly improved the memory loss and spatial learning ability of AD mice. Western blotting and immunofluorescence staining further confirmed that CalD effectively reduced Aβ deposition and inhibited the excessive activation of microglia. Network pharmacology analysis found that the mechanism of action of CalD mainly involved inflammatory signaling pathways and sphingolipid metabolism. Subsequently, in vivo and in vitro experiments confirmed that CalD could inhibit the excessive activation of the TLR4/NF-κB/NLRP3 signaling pathway and restore the ceramide homeostasis in AD mice. On this basis, molecular docking and small interfering RNA experiments further clarified that CalD played an anti-inflammatory and regulatory role in sphingolipid metabolism by targeting CERT. In summary, these findings indicate that CalD exerts neuroprotective effects by modulating neuroinflammation and ceramide metabolic dysregulation, suggesting that CalD has therapeutic potential in AD.

Keywords:  Alzheimer's disease; Calcaratarin D; Ceramides; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1016/j.expneurol.2025.115585
Int J Biol Macromol. 2025 Nov 27. pii: S0141-8130(25)09744-2. [Epub ahead of print] 149187

Neuronal alpha-synuclein-mediated autophagy drives lipid droplets accumulation in astrocytes and microglia and aggravates ischemic stroke.

Wenqiang Xin, Wei Wei, Xiaoyue Luo, Zhongnan Hao, Lin Zhang, Yuanyang Zeng, Hao Wan, Shangsong Yang, Xiaobin Shang, Meihua Li, Zhipeng Xiao, Yongli Pan.

   BACKGROUND: Lipid droplets (LDs) agglomeration in glial cells after stroke contributes to cellular dysfunction and neuronal injury. Alpha-synuclein has been identified as a critical regulator in the uptake and metabolism of fatty acids across various neurological disorders. Moreover, alterations in autophagic function can impact the agglomeration of LDs following a stroke. It is also well-established that alpha-synuclein is directly involved in neuronal autophagy. Although substantial research has been conducted on the relationship between alpha-synuclein and lipid metabolism, the precise mechanisms by which alpha-synuclein modulates lipid metabolism in glial cells post-stroke are not yet fully understood.
METHODS: Primary neurons and glial cells from neonatal mice were used to establish in vitro oxygen-glucose deprivation/reoxygenation and neuron-glia co-culture models. In vivo studies employed alpha-synuclein knockdown mice subjected to middle cerebral artery occlusion. Analysis of readout parameters using various techniques, including qRT-PCR, immunofluorescence, western blot assays, phagocytosis and behavioral tests. Utilizing both in vitro and in vivo stroke models, we investigated how alpha-synuclein modulates the interactions between neurons and microglia/astrocytes.
RESULTS: We found that ischemic stroke induces LD agglomeration, triggers autophagy, and increases alpha-synuclein levels. Knockdown of alpha-synuclein reduced LD formation, restored autophagic balance, and improved neurological outcomes. In co-culture, silencing neuronal alpha-synuclein or enhancing neuronal autophagy decreased LD accumulation and modified LD-associated protein expression in microglia and astrocytes. Moreover, neuronal alpha-synuclein and autophagy regulation modulated glial phagocytic activity without directly altering glial autophagy. Additionally, changes in LD accumulation appear to play a pivotal role in mediating interactions between glial cells and neurons, thereby influencing cell viability and autophagy. Consistent with these findings, treatment with alpha-synuclein siRNA alleviates stroke-induced neurological deficits.
CONCLUSION: Alpha-synuclein regulates lipid metabolism and phagocytic activity in glial cells through autophagy mechanisms under ischemic conditions, providing new insight into therapeutic strategies for stroke.

Keywords:  Alpha-synuclein; Astrocyte; Ischemic stroke; Lipid droplets; Lipid metabolism; Microglia

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149187
Acta Neuropathol Commun. 2025 Dec 01. 13(1): 245

Human neural stem cell-derived exosomes promote functional recovery in subarachnoid hemorrhage via bdnf/trkb pathway activation and astrocyte modulation.

Xiaobin Zhang, Fangkun Jing, Jianan Li, Yang Bai, Chen Guo, Hai Jin, Yushu Dong, Guobiao Liang.

  Subarachnoid hemorrhage (SAH) is a devastating neurological condition with limited therapeutic options for mitigating secondary brain injury. This study investigates the neuroprotective potential of exosomes derived from human neural stem cells (hNSC-exo) in a rat SAH model, focusing on their molecular mechanisms through single-cell RNA sequencing (scRNA-seq) and transcriptomic profiling. This study demonstrated that hNSC-exo administration significantly ameliorated neurological deficits, reduced blood-brain barrier (BBB) disruption, and attenuated neuronal damage post-SAH. Behavioral assessments revealed improved cognitive and motor recovery in hNSC-exo-treated rats, supported by histopathological evidence of preserved neuronal architecture and reduced edema. scRNA-seq analysis revealed a marked increase in astrocyte proportions and vitality following hNSC-exo treatment, alongside suppression of neurotoxic microglial activation. Transcriptomic profiling identified the BDNF/TRKB signaling pathway as a critical mediator, with hNSC-exo upregulating BDNF and TRKB expression both in vivo and in vitro. Functional validation confirmed that hNSC-exo enhanced astrocyte survival via BDNF/TRKB activation, while knockdown of BDNF or TRKB reversed these protective effects. Furthermore, hNSC-exo mitigated neuroinflammation by reducing pro-inflammatory cytokines (TNF-α, IL-18) and microglial C1q expression. These findings highlight hNSC-exo as a novel therapeutic strategy for SAH, leveraging astrocyte-mediated neuroprotection and BDNF/TRKB pathway activation to counteract secondary injury. This study provides mechanistic insights into exosome-based therapies and underscores their potential for clinical translation in cerebrovascular disorders.

Keywords:  Astrocyte activation; BDNF/TRKB signaling; Neural stem cell exosomes; Neuroinflammation; Subarachnoid hemorrhage

DOI:  https://doi.org/10.1186/s40478-025-02155-0
J Neuroinflammation. 2025 Dec 02. 22(1): 282

Extracellular vesicle-derived miR21 of non-tumoral origin as early diagnostic marker of glioma.

Mariassunta De Luca, Arianna Rinaldi, Arianna Ioni, Anaïs Oudin, Andrea Scafidi, Aurélie Poli, Laura Vilardo, Anna Golebiewska, Igea D'Agnano, Alessandro Michelucci, Cristina Limatola, Myriam Catalano.

   BACKGROUND: Extracellular vesicles (EVs) are key elements in intercellular communication and are released into body fluids by all cells in physiological and pathological conditions. In brain tumors, EVs facilitate the bidirectional communication between neoplastic cells and the tumor microenvironment, promoting tumor progression and immune evasion. Among the various components of the EVs, microRNAs (miRs) act as potent regulators of gene expression. In particular, miR21 has gained attention as both a promising diagnostic biomarker and a key contributor to GBM progression.
METHODS: This study employed content analysis of miRs in EVs isolated from the brain, plasma, and urine of glioma-bearing mice.
RESULTS: Seven days after glioma cell injection, miR21 was the most highly expressed miR in both the brain and biofluids. Notably, its overexpression was particularly prominent in medium/large EVs. Co-culture experiments revealed that the early source of this marker is primarily microglia, rather than tumor cells.
CONCLUSION: These data point out the potential of miR21 as early biomarker for glioma diagnosis and disease monitoring, emphasizing the role of non-tumoral cells, particularly microglia, as rapidly reacting elements in the context of gliomas.

Keywords:  Extracellular vesicles; Glioma; Liquid biopsy; MiR21; Microglia

DOI:  https://doi.org/10.1186/s12974-025-03605-1