bims-microg Biomed News
on Microglia in health and disease
Issue of 2025–11–30
twenty papers selected by
Marcus Karlstetter, Universität zu Köln
  1. IL-12 ameliorates diabetic retinal neurodegeneration by activating microglial phagocytosis via the TREM2/DAP12 pathway.
  2. A myeloid trisomy 21-associated gene variant is protective from Alzheimer's disease.
  3. Microglial CLEC7A restrains amyloid beta plaque pathology in a mouse model of Alzheimer's disease.
  4. Activated microglial exosomes enhance α-Synuclein internalization and accelerate neurodegeneration in lewy body dementia.
  5. FOXA2 regulated by HDAC3-mediated deacetylation attenuates neuropathic pain by modulating microglial lipid metabolism and synaptic pruning dysregulation.
  6. Spatial and single-cell transcriptomics reveal the reorganization of cerebellar microglia with aging.
  7. Human umbilical MSC-derived exosomes improve intracerebral hemorrhage recovery via SIRT1-driven suppression of NF-κB/NOS2 signaling: coordinating microglial homeostasis and neuroprotection.
  8. Protocol for in vitro phagocytosis assay for primary mouse microglia and human embryonic stem cell-derived microglia.
  9. Study on the Mechanism of Acanthopanax senticosus Extract Intervening in the Regulation of Parkinson's Disease by BV2 Microglial Cell-Derived Exosomes.
  10. Direct Reprogramming of Microglia into Neurons.
  11. Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice.
  12. NRF2 activation by CDDO-Im regulates inflammatory and autophagy pathways in human microglial cells.
  13. Ciwujianoside C Attenuates Cerebral Ischemia-Reperfusion Injury by Suppressing Ferroptosis via NNAT-Mediated Inhibition of NF-κB Signaling.
  14. Spinal microglial membrane glucocorticoid receptors regulate anti-hypersensitivity by stimulating dynorphin A expression.
  15. Metabolic reprogramming and altered ATP content impair neuroprotective functions of microglia in β-glucocerebrosidase deficiency models.
  16. Midkine-Mediated Microglia Activation after Renal Injury Promotes Cognitive Impairment Following Ischemic Renal Injury.
  17. The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia.
  18. Microglial estrogen receptor 1 signal designates sexual dimorphism of AQP4 antibody-induced neuroinflammation and demyelination.
  19. Midbrain extracellular matrix and microglia are associated with cognition in aging mice.
  20. Hippocampal neural stem cell-derived extracellular vesicles modulate microglia to promote resilience against tau oligomers.
  1. Mol Neurobiol. 2025 Nov 29. 63(1): 215
    IL-12 ameliorates diabetic retinal neurodegeneration by activating microglial phagocytosis via the TREM2/DAP12 pathway.
    Wanyi Fang, Shanshan Liu, Yifei Wu, Ting Chen, Xiaohe Lu, Hui Chen.
      Diabetic retinopathy (DR) is a common neurovascular complication of diabetes and a leading cause of vision loss in the advanced stages. Identifying therapeutic targets to prevent early progression of DR is critical for preserving visual function. Interleukin-12 (IL-12) has emerged as a potential therapeutic agent for early-stage diabetic retinal neurodegeneration. In this study, diabetic mouse models were established, followed by intravitreal injection of IL-12 to evaluate its effects using hematoxylin and eosin staining and RNA sequencing. IL-12 treatment partially prevented the thinning of the nerve fiber layer, ganglion cell layer, and total retina. Bioinformatics analysis of RNA sequencing data revealed enrichment of microglial signatures and enhanced phagocytic function. Western blotting analysis showed that IL-12 promoted the phosphorylation of signal transducer and activator of transcription 4 (STAT4) in microglia. Bioinformatics and quantitative reverse transcription polymerase chain reaction analyses demonstrated that STAT4 activation upregulated the transcription of phagocytosis-related genes, including triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12). In vitro and in vivo experiments confirmed that IL-12 upregulates the TREM2/DAP12 signaling pathway on the microglial membrane, enhancing microglial proliferation and phagocytic activity under high-glucose conditions. These findings indicated that IL-12 mitigates early neural injury in DR by promoting microglial phagocytosis through the upregulation of TREM2/DAP12.
    Keywords:  DAP12; Interleukin-12; Microglia; Retina; TREM2
    DOI:  https://doi.org/10.1007/s12035-025-05512-1
  2. Nat Neurosci. 2025 Nov 24.
    A myeloid trisomy 21-associated gene variant is protective from Alzheimer's disease.
    Mengmeng Jin, Ziyuan Ma, Rui Dang, Haiwei Zhang, Rachael Kim, Haipeng Xue, Jesse Pascual, Hanwen Yu, Ava V Papetti, Yan Liu, Steven Finkbeiner, Elizabeth Head, Ying Liu, Peng Jiang.
      Alzheimer's disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer's disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience. Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4-10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence. CSF2RB A455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies.
    DOI:  https://doi.org/10.1038/s41593-025-02117-8
  3. Alzheimers Dement. 2025 Nov;21(11): e70943
    Microglial CLEC7A restrains amyloid beta plaque pathology in a mouse model of Alzheimer's disease.
    Aman Mangalmurti, Kristine E Zengeler, Ava Hollis, Emily Golden, Gabrielle Riddlemoser, John R Lukens.
       INTRODUCTION: CLEC7A is a surface receptor that is highly upregulated on microglia in many Alzheimer's disease (AD) models. Little is known about the role that microglial CLEC7A signaling plays in AD-related pathogenesis.
    METHODS: We utilized an inducible, central nervous system (CNS) macrophage-specific knockout of Clec7a to evaluate the role of CLEC7A in the 5xFAD mouse model of AD at 5 months of age. We used immunofluorescence microscopy, single-nuclei RNA sequencing, along with biochemical assays, to evaluate plaque burden, microglial activity, and neuronal health.
    RESULTS: CNS macrophage-targeted deletion of CLEC7A in 5xFAD mice led to a twofold increase in plaque burden, exacerbated neuritic dystrophy, and altered the expression of neuronal health genes, but did not appreciably impact microglial activation, plaque engulfment, or disease-associated microglia acquisition.
    DISCUSSION: These findings identify protective roles for CLEC7A in AD-related amyloidosis and suggest that CLEC7A-targeting therapeutics may offer promising strategies for treatment of AD.
    HIGHLIGHTS: Conditional loss of CLEC7A in central nervous system (CNS) macrophages of 5xFAD mice results in increased amyloid beta deposition. Loss of CLEC7A does not alter the disease-associated microglia transcriptional program or affect the recruitment of microglia to plaque surfaces. Exacerbation of amyloid deposition with loss of CNS-macrophage CLEC7A is associated with worsened neuronal health highlighted by increased neuritic dystrophy.
    Keywords:  Alzheimer's disease; CLEC7A; amyloid beta; amyloidosis; innate immunity; microglia; neurodegenerative disease; neuroimmunology
    DOI:  https://doi.org/10.1002/alz.70943
  4. J Nanobiotechnology. 2025 Nov 25. 23(1): 740
    Activated microglial exosomes enhance α-Synuclein internalization and accelerate neurodegeneration in lewy body dementia.
    Minjie Zhang, Tongyao You, Min Guo, Yichen Zhao, Weiwei Shen, Yingzhe Wang, Yanfeng Jiang, Qiang Dong, Jintai Yu, Mei Cui, Yanxin Zhao.
      Lewy body dementia (LBD), which includes Parkinson's disease dementia and dementia with Lewy bodies, is characterized by progressive cognitive decline, α-synuclein (α-Syn) aggregation, and concurrent microglial activation and neuroinflammation. The nucleus basalis of Meynert (NBM), the primary source of cortical cholinergic input, plays a key role in cognitive function and is particularly affected in LBD. Cholinergic neurons within the NBM are highly vulnerable to Lewy body pathology, yet the underlying mechanisms remain poorly understood. In this study, we employed a mouse model with PFF injections into the NBM to investigate how microglia and their exosomes influence α-Syn pathology. We found that exosomes derived from activated microglia exacerbate α-Syn deposition and cognitive deficits, whereas microglial depletion mitigates these pathological changes. In vitro, activated microglial exosomes enhanced the uptake of exogenous α-Syn by cholinergic neurons. Mechanistically, we discovered that microglial exosomes can transfer bioactive membrane receptors to neurons. Focusing on lymphocyte-activation gene 3 (LAG3), a receptor critical for α-Syn internalization, we demonstrated that LAG3 is abundant in exosomes from activated-but not resting-microglia. These exosomes deliver LAG3 to neuronal membranes via an endosomal recycling pathway, a process facilitated by elevated cholesterol content, thereby promoting α-Syn uptake. Together, these findings indicate that microglial exosomes function not only as carriers of signaling molecules but also as vectors for receptor transfer, reshaping neuronal membrane composition. Our results provide a mechanistic explanation for the heightened vulnerability of NBM cholinergic neurons in LBD and reveal a novel pathway in which LAG3-rich microglial exosomes drive neuronal α-Syn internalization, advancing our understanding of neurodegeneration and identifying potential therapeutic targets.
    Keywords:  Exosome; Lewy body dementia; Microglia; Nucleus basalis of meynert
    DOI:  https://doi.org/10.1186/s12951-025-03838-5
  5. J Neuroinflammation. 2025 Nov 26. 22(1): 280
    FOXA2 regulated by HDAC3-mediated deacetylation attenuates neuropathic pain by modulating microglial lipid metabolism and synaptic pruning dysregulation.
    Hui Zeng, Bo Wang, ZhiLin Huang, LiJie Gao, Yao Xiao, XinLi Liu, Yin Xu, ZiWei Hu, JiaHui Pang, YouXin Yu, YanWu Guo, Wen Wu.
      
    Keywords:  FOXA2; Lipid metabolism; Microglia; Neuropathic pain; Synaptic pruning
    DOI:  https://doi.org/10.1186/s12974-025-03601-5
  6. Cell Rep. 2025 Nov 25. pii: S2211-1247(25)01396-8. [Epub ahead of print]44(12): 116624
    Spatial and single-cell transcriptomics reveal the reorganization of cerebellar microglia with aging.
    Andy P Tsai, Douglas E Henze, Eduardo Ramirez Lopez, James Haberberger, Chuanpeng Dong, Nannan Lu, Micaiah Atkins, Emma K Costa, Amelia Farinas, Hamilton Se-Hwee Oh, Patricia Moran-Losada, Yann Le Guen, Alina Isakova, Stephen R Quake, Tony Wyss-Coray.
      The cerebellum, essential for motor coordination and increasingly recognized for its role in cognition, is typically considered more resilient to aging and largely spared from hallmark Alzheimer's disease (AD) pathology. However, transcriptomic analyses across fifteen mouse brain regions revealed that the cerebellum undergoes some of the earliest and most pronounced age-related changes. To investigate cerebellar aging, we applied single-nucleus RNA sequencing (RNA-seq), microglial bulk RNA-seq, and multiplexed error-robust fluorescence in situ hybridization (MERFISH)-based spatial transcriptomics. Microglia showed the most prominent changes, including elevated expression of a neuroprotective signature and reduced expression of a lipid-droplet-accumulating signature compared to hippocampal microglia. Spatial analyses further revealed that aged cerebellar microglia were positioned in close proximity to granule cells. Utilizing this relationship, we identified a proximity-dependent transcriptional state defined by the neuron-associated microglial signature. This signature reveals a region-specific microglial adaptation, highlighting cerebellar reorganization with age and potential resilience to AD.
    Keywords:  CP: neuroscience; brain aging; cerebellum; disease susceptibility; hippocampus; lipid-droplet-accumulating microglia; multi-omics; neuron-associated microglia; neuroprotective microglia; region- and age-specific transcriptional profiles; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116624
  7. J Transl Med. 2025 Nov 27. 23(1): 1361
    Human umbilical MSC-derived exosomes improve intracerebral hemorrhage recovery via SIRT1-driven suppression of NF-κB/NOS2 signaling: coordinating microglial homeostasis and neuroprotection.
    Dewen Ru, Jun Zhang, Zengyu Zhang, Lichao Wei, Heng Li, Yuqi Wang, Heng Lin, Chen Lin, Yanna Ma, Jin Hu, Ersong Wang.
      
    Keywords:  Hemorrhagic stroke; Microglia; NF-κB/NOS2 signaling; Neuroinflammation; hUMSC-exosomes
    DOI:  https://doi.org/10.1186/s12967-025-07430-1
  8. STAR Protoc. 2025 Nov 24. pii: S2666-1667(25)00625-2. [Epub ahead of print]6(4): 104219
    Protocol for in vitro phagocytosis assay for primary mouse microglia and human embryonic stem cell-derived microglia.
    Beika Zhu, Alicia L Thurber, Xianhua Piao.
      Microglia, the resident immune cells of the brain, maintain brain health by clearing detrimental debris, including amyloid-β (Aβ). Here, we present a protocol for assessing Aβ uptake by primary mouse microglia and human embryonic stem cell-derived microglia using an in vitro phagocytosis assay. We describe procedures for pHrodo-labeled oligomeric Aβ treatment and real-time signal detection using the Incucyte SX5 system. We also detail steps for microglia culture, Aβ labeling, and quantification of phagocytosis over time. For complete details on the use and execution of this protocol, please refer to Zhu et al.1.
    Keywords:  Cell-based Assays; Immunology; Model Organisms; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2025.104219
  9. Mol Neurobiol. 2025 Nov 24. 63(1): 159
    Study on the Mechanism of Acanthopanax senticosus Extract Intervening in the Regulation of Parkinson's Disease by BV2 Microglial Cell-Derived Exosomes.
    Ningxia Lu, Yehao Wang, Yi Lu, Fang Lu, Shumin Liu.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. With the intensification of population aging, its incidence rate continues to rise. Microglia play a significant role in regulating neuronal functions. As carriers of intercellular communication, exosomes can mediate intercellular information transmission and signal regulation. This study aimed to explore the molecular mechanism by which Acanthopanax senticosus extract (AS) interferes with the PD process by regulating BV2 microglial cells exosome communication. A PD-related inflammation model was established by inducing BV2 microglial cells activation with lipopolysaccharide (LPS). Exosomes derived from microglia were isolated by ultracentrifugation. The exosomes were co-cultured with the SHSY5Y-flag-snca cells to detect the expression levels of α-synuclein(α-syn) and tyrosine hydroxylase (TH) in these cells. Transcriptome sequencing using exosomes revealed that the mechanism by which AS treats PD involves the regulation of the long noncoding RNA-microRNA-messenger RNA network in exosomes, and the expression of target genes differentially expressed by exosomes was verified by the RT-qPCR method. This study explored at the molecular level the mechanism by which AS regulates BV2 microglial cells exosomes in intercellular communication therapy for PD, providing new research directions and theoretical basis for finding therapeutic targets for PD.
    Keywords:   Acanthopanax senticosus ; BV2 microglial cell–derived exosomes; Parkinson’s disease; long noncoding RNA microRNA–messenger RNA network
    DOI:  https://doi.org/10.1007/s12035-025-05468-2
  10. Methods Mol Biol. 2026 ;2974 153-161
    Direct Reprogramming of Microglia into Neurons.
    Kanae Matsuda-Ito, Eriko Hatai, Takashi Irie, Taito Matsuda, Kinichi Nakashima.
      In recent years, direct reprogramming methods have attracted attention as they can bypass the immature stem cell state and directly induce the desired cell type by introducing key transcription factors into somatic cells. This technique offers advantages such as shorter induction times compared to inducing the desired cells from induced pluripotent stem cells. Furthermore, this approach enables the provision of the requisite cell types to patients requiring treatment without eliciting an immune rejection response. Microglia, the resident immune cells of the central nervous system, exhibit high proliferative and regenerative capacities, allowing them to repopulate even after almost complete depletion. In response to injury, microglia accumulate in damaged brain regions and become the primary cell type that forms the glial scar. Given these properties, microglia are promising candidates for direct reprogramming into neurons in the injured area without depleting cell sources. This chapter outlines a protocol for directly reprogramming cortical microglia into neurons, utilizing primary culture and lentiviral-mediated gene transfer techniques.
    Keywords:  Direct reprogramming; Infection; Lentivirus; Microglia; Neuron; Primary culture
    DOI:  https://doi.org/10.1007/978-1-0716-4807-0_13
  11. Geroscience. 2025 Nov 22.
    Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice.
    Ramkumar Thiyagarajan, Rupadevi Muthaiah, Bhavana Sreevelu, Owen P Treanor, Yonas Redae, Reem Berman, Anna L Davis, Nanda Yellapu, Spencer R Rosario, Lee D Chaves, Kenneth L Seldeen, Bruce R Troen.
      Cognitive impairment affects 1 in 6 individuals over 60, with over 75 million projected by 2030. Age-related changes in microglial function and declining nicotinamide adenine dinucleotide (NAD+) levels may contribute to cognitive decline. Although nicotinamide riboside (NR) supplementation can restore NAD+ levels in aged mice, its effects on microglial phenotype and cognition during normal aging remain unclear. We assessed cognitive function, neuroinflammation, and microglial gene expression in 6-month (Young) and 22-month (Aged) mice, along with aged mice supplemented with NR (Aged + NR; 400 mg/kg body weight) for 8 weeks. Aged mice exhibited impaired cognition and increased gene expression related to neuroinflammation. NR supplementation improved or prevented the decline in nest-building ability, Y-maze spontaneous alternation, and novel object recognition, which are reflective of instrumental activities of daily living, spatial working memory, and recognition memory. NR supplementation diminished microglial (IBA1) and astrocytic (GFAP) activation, resembling the young phenotype. Gene expression profiling revealed reduced microglial activation, inflammatory pathways, and chemokine production in Aged + NR mice, along with upregulation of genes associated with learning, memory, and gliogenesis. NR lowered transcriptional signatures from age-dependent (ADEM) and disease-associated (DAM) microglia and enhanced homeostatic state profiles. Metabolic pathway analysis of microglial transcripts indicated that NR suppressed age-induced increases in fatty acid metabolism. This was supported by immunostaining, which showed reduced lipoprotein lipase (LPL), a DAM marker, in the cortex and hippocampus. Overall, NR appeared to mitigate age-related cognitive decline by shifting microglial gene expression and metabolism toward a younger phenotype, suggesting potential therapeutic relevance for healthy brain aging.
    Keywords:  Aging; Cognition decline; Disease-associated microglia; Microglia; NAD metabolism
    DOI:  https://doi.org/10.1007/s11357-025-01959-1
  12. Free Radic Biol Med. 2025 Nov 21. pii: S0891-5849(25)01391-7. [Epub ahead of print]243 318-337
    NRF2 activation by CDDO-Im regulates inflammatory and autophagy pathways in human microglial cells.
    Ching-Tung Chu, Akira Uruno, Takafumi Suzuki, Keiko Taguchi, Liam Baird, Fumiki Katsuoka, Masayuki Yamamoto.
      Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles, accompanied by elevated oxidative stress and inflammation. Microglia, the resident macrophages in the brain, play a key protective role by clearing plaques and damaged neurons. NRF2 (Nuclear factor erythroid 2-related factor 2) is a master regulator of cytoprotection against oxidative stress, whose activation alleviates oxidative damage, neuroinflammation, and cognitive deficits in AD models. However, direct targets of NRF2 in microglia remain unclear. In this study, we demonstrate that NRF2 activation by CDDO-Im significantly suppresses inflammation in human microglial cells (HMC3) stimulated by IFN-γ or Aβ. Through integrative RNA-sequencing and ChIP-sequencing analysis of NRF2, we identified five representative direct NRF2 target genes involved in inflammation (e.g., IL6, CDK6) and another five related to autophagy (e.g., TFE3, SQSTM1). Importantly, we also found that CDDO-Im treatment enhances autophagy as evidenced by an increased LC3-II/LC3-I ratio. Public single-cell transcriptomic data further underscored the critical role of microglia in NRF2-mediated autophagy regulation within AD brains. Together, our findings reveal new direct NRF2 target genes, highlight the dual role of NRF2 in suppressing inflammation and enhancing autophagy, and thus provide novel insights for therapeutic interventions in AD.
    Keywords:  Alzheimer's disease (AD); Amyloid beta (Aβ); Interferon-gamma (IFN-γ); Microglia; NRF2 activation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.046
  13. Neurochem Res. 2025 Nov 29. 51(1): 6
    Ciwujianoside C Attenuates Cerebral Ischemia-Reperfusion Injury by Suppressing Ferroptosis via NNAT-Mediated Inhibition of NF-κB Signaling.
    Weichuan Dai, Yingxian Chen, Wenhua Cai, Yuyan Zhu, Xieli Guo.
      Cerebral ischemia-reperfusion injury (CIRI) involves oxidative stress, inflammation, and regulated cell death, among which ferroptosis has emerged as a key contributor. However, therapeutic strategies targeting ferroptosis remain limited. This study investigated whether Ciwujianoside C (CC), a triterpenoid saponin from Acanthopanax senticosus, protects against CIRI by modulating ferroptosis via the NNAT/NF-κB pathway. In MCAO/R rats, CC reduced infarct size, improved neurological scores, and ameliorated oxidative stress and ferroptosis markers. In BV2 microglia and HT22 cells (a mouse hippocampal neuronal cell line) subjected to OGD/R, CC enhanced cell viability, decreased iron accumulation, and restored GPX4 and FTH1 expression while inhibiting NF-κB activation. Importantly, NNAT knockdown abolished these protective effects, demonstrating NNAT as a critical mediator. These findings reveal that CC protects against CIRI by suppressing ferroptosis through the NNAT/NF-κB axis, highlighting NNAT as a potential therapeutic target in CIRI.
    Keywords:  Cerebral ischemia-reperfusion injury; Ciwujianoside C; Ferroptosis; NNAT/NF-κB signaling; Neuroprotection
    DOI:  https://doi.org/10.1007/s11064-025-04622-5
  14. Eur J Pharmacol. 2025 Nov 21. pii: S0014-2999(25)01116-1. [Epub ahead of print]1010 178362
    Spinal microglial membrane glucocorticoid receptors regulate anti-hypersensitivity by stimulating dynorphin A expression.
    Le Ma, Jinbao Wei, Meng-Yan Deng, Khalil Ali Ahmad, Jinlu Huang, Meng-Jing Zhao, Xinyan Li, Yemeng Mao, Yong-Xiang Wang, Jinghong Chen.
      Previous studies have speculated the existence of a specific expression of the glucocorticoid receptor (GR) that is independent of the nuclear transcription mechanism, this type of receptor may play a decisive role in analgesic effects. The effects were determined by behavioral assessment, whole-cell recording, immunofluorescence staining, and quantitative PCR. A single intrathecal agonism of dexamethasone (DEX) and membrane-impermeable DEX-BSA exerted time-dependent anti-hypersensitivity effects and regulated spinal functional connectivities in formalin and neuropathic rats, respectively. Both DEX and DEX-BSA significantly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) in a dosage-dependent manner. Pharmacological inhibition of GRs, dynorphin A, kappa-opioid receptors (KORs), and microglia effectively reversed the inhibitory effects of DEX and DEX-BSA on mEPSCs. Protopanaxadiol (PPD), an analogue of DEX, exhibited similar inhibitory effects on mEPSCs, without affecting the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Molecular docking analysis indicated an effective binding of DEX and PPD to GRs. GRs were mainly colocalized with the nuclear biomarker DAPI in the spinal cord. Importantly, scatter GRs, particularly in the substantia gelatinosa, were colocalized with microglia. Pharmacological stimulation of GR expression in neuronal nuclei did not alter the frequency and amplitude of mEPSCs in neuropathic rats. In addition, intrathecal DEX, DEX-BSA, and PPD also suppressed pain in female rats. DEX exerts antinociceptive effects by activating spinal microglial membrane GRs and dynorphin A release, thereby stimulating KORs-mediated inhibition of glutamatergic transmission.
    Keywords:  Anti-hypersensitivity; Dexamethasone (DEX); Dynorphin A; Glucocorticoid receptors; Glutamatergic transmission; Microglia
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178362
  15. J Neuroinflammation. 2025 Nov 25. 22(1): 279
    Metabolic reprogramming and altered ATP content impair neuroprotective functions of microglia in β-glucocerebrosidase deficiency models.
    Electra Brunialti, Alessandro Villa, Eva M Szego, Pietro La Vitola, Denise Drago, Radmila Pavlovic, Laura Fontana, Doga Tuna, Alessia Panzeri, Clara Meda, Christin Weissleder, Ornella Rondinone, Mattia Pitasi, Monica Miozzo, Michela Deleidi, Annapaola Andolfo, Donato A Di Monte, Paolo Ciana.
      
    Keywords:  ATP; Energetic failure; Gaucher’s disease; Microglia; Neuroprotection; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s12974-025-03616-y
  16. Adv Sci (Weinh). 2025 Nov 23. e07832
    Midkine-Mediated Microglia Activation after Renal Injury Promotes Cognitive Impairment Following Ischemic Renal Injury.
    Li Lu, Bixiao Liu, Yu Yang, Tao Meng, Yuanyuan Chang, Yao Peng, Jia Guo, Zhuqing Wang, Hongqian Guo, Liuhua Zhou, Xiaozhi Zhao.
      Acute kidney injury (AKI) is associated with a high prevalence of cognitive impairment, the underlying mechanisms remain elusive. This study explores the role of midkine (MDK), upregulated in renal injury, in mediating cognitive dysfunction following post-ischemic renal injury. Using a mouse model of unilateral renal ischemia-reperfusion injury, cognitive deficits and blood-brain barrier disruption is observed. Single-cell RNA sequencing and ligand-receptor interaction analysis reveals a strengthened MDK-LRP1 axis in both the kidneys and hippocampus of mice subjected to ischemic renal injury. MDK, mainly from injured renal tubular cells and fibroblasts, is enriched in peripheral blood and the hippocampus, correlating with increased activation of hippocampal microglia and upregulation of c. It is demonstrated that MDK internalization into microglia via LRP1 upregulated P2ry12 expression, promoting microglial activation and phagocytosis. Inhibiting renal MDK expression with shRNA adenovirus ameliorated cognitive dysfunction and attenuated microglial activation after ischemic renal injury. These findings suggest the MDK-LRP1 pathway is a key mediator of cognitive dysfunction following ischemic renal injury and a potential therapeutic target for mitigating cognitive decline in AKI patients. It provides a mechanistic link between renal injury, neuroinflammation, and cognitive deficits, highlighting the potential of targeting MDK-LRP1 signaling to address cognitive impairment after ischemic renal injury.
    Keywords:  acute kidney injury cognitive impairment; microglia activation; midkine, P2ry12
    DOI:  https://doi.org/10.1002/advs.202507832
  17. Nat Neurosci. 2025 Nov 24.
    The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia.
    Giulia Albertini, Magdalena Zielonka, Marie-Lynn Cuypers, An Snellinx, Ciana Xu, Suresh Poovathingal, Marta Wojno, Kristofer Davie, Veerle van Lieshout, Katleen Craessaerts, Leen Wolfs, Emanuela Pasciuto, Tom Jaspers, Katrien Horré, Lurgarde Serneels, Mark Fiers, Maarten Dewilde, Bart De Strooper.
      Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41593-025-02125-8
  18. Cell Rep. 2025 Nov 26. pii: S2211-1247(25)01408-1. [Epub ahead of print]44(12): 116636
    Microglial estrogen receptor 1 signal designates sexual dimorphism of AQP4 antibody-induced neuroinflammation and demyelination.
    Zhijie Zhou, Zhangyuzi Deng, Yingying Huang, Jian Chen, Jing Yang, Ying Cao.
      Neuromyelitis optica spectrum disorder, often linked to autoimmune antibodies against aquaporin-4 (AQP4), is a demyelinating disease exhibiting a profound sex bias in female patients. However, the pathophysiological mechanism underlying this clinical manifestation remains to be better understood. In this study, we observe a higher extent of neuroinflammation and demyelination in female mice than in males with the AQP4 antibody-induced disease model. Of importance is that sex hormone depletion in ovariectomized female mice is sufficient to mitigate the disease severity, while estradiol replacement in castrated male mice exacerbates these neuropathological features. We then demonstrate that microglia predominantly express estrogen receptor 1 (Esr1) and that specific deletion of Esr1 inhibits microglia-mediated neuroinflammation and reduces demyelination. Moreover, the administration of fulvestrant, a clinically approved estrogen receptor antagonist, can effectively ameliorate the mouse disease model. These results have elucidated a critical, proinflammatory role of the microglial Esr1 signal in AQP4 antibody-induced neuroinflammation and demyelination with clinical implications.
    Keywords:  CP: immunology; CP: neuroscience:; estrogen receptor 1; fulvestrant; microglia; neuromyelitis optica spectrum disorder; sexual dimorphism
    DOI:  https://doi.org/10.1016/j.celrep.2025.116636
  19. Nat Commun. 2025 Nov 27.
    Midbrain extracellular matrix and microglia are associated with cognition in aging mice.
    Daniel T Gray, Abigail Gutierrez, Yasaman Jami-Alahmadi, Vijaya Pandey, Lin Pan, Ye Zhang, James A Wohlschlegel, Ross A McDevitt, Lindsay M De Biase.
      Synapse dysfunction is tightly linked to cognitive changes during aging. Emerging evidence suggests that microglia and the extracellular matrix (ECM) can potently regulate synapse integrity and plasticity. Yet the brain ECM, and its relationship with microglia, synapses, and cognition during aging remains virtually unexplored. In this study we combine ECM-optimized proteomic workflows with histological analyses in aging mice and discover regional differences in ECM composition and aging-induced ECM remodeling across basal ganglia nuclei. Moreover, we combine two distinct behavioral classification strategies with fixed-tissue confocal imaging and proteomic analysis and identify relationships between the hyaluronan- and proteoglycan-rich ECM and cognitive aging phenotypes. Finally, we provide evidence that aging midbrain microglia lose capacity to interact with and regulate the ECM, and that these aging-associated microglial changes are accompanied by local ECM accumulation and worse behavioral performance. Together, these observations indicate that changing microglia-ECM-synapse interactions contribute to cognitive functioning during healthy aging.
    DOI:  https://doi.org/10.1038/s41467-025-66434-z
  20. Neural Regen Res. 2025 Nov 25.
    Hippocampal neural stem cell-derived extracellular vesicles modulate microglia to promote resilience against tau oligomers.
    Salvatore Saieva, Pietro Scaduto, Anna Fracassi, Jutatip Guptarak, Wen-Ru Zhang, Kathia Johnson, Daniel C Jupiter, Michela Marcatti, Olga Zolochevska, Giulio Taglialatela, Maria-Adelaide Micci.
       ABSTRACT: Neural stem cells and adult hippocampal neurogenesis modulate synaptic plasticity and cognitive function. Neural stem cells secrete extracellular vesicles - microvesicles carrying biomolecular cargos - that modulate the function of other cells and contribute to homeostasis and plasticity in the central nervous system. Alzheimer's disease is marked by a reduction of neural stem cells in the hippocampus dentate gyrus. While increased neural stem cells often correlate with better learning and memory, neurogenesis alone does not always preserve these processes, indicating that other mechanisms involving neural stem cells support memory. It has been shown that intracerebroventricular delivery of neural stem cell-derived small extracellular vesicles in wild-type mice reduces cognitive decline and toxic oligomer binding to synapses. We hypothesize that adequate neural stem cell numbers support neural stem cell-derived small extracellular vesicles protection of synapses against Alzheimer's disease toxic oligomers. Here, we show that elements of immune response in the central nervous system, particularly microglia, may contribute to this protective effect. Specifically, fluorescent-labeled small extracellular vesicles injected into wildtype mice brains were taken up by microglia, with only neural stem cell-derived small extracellular vesicles causing increased microglial activation, indicated by CD68 immunostaining. RNA-sequencing data showed selective activation of immune pathways in microglia by neural stem cell-derived small extracellular vesicles, leading to greater activation and higher Tau uptake 24 hours post-neural stem cell-derived small extracellular vesicle administration. Single-nuclei RNAsequencing of hippocampal microglia gene revealed modulation related to lysosomal activity, supporting neural stem cell-derived small extracellular vesicleinduced neuroprotection via microglia. This study uncovers a novel mechanism through which neural stem cell-derived small extracellular vesicles enhance microglial activity and provide neuroprotection in the hippocampus. Our data demonstrates that neural stem cell-derived small extracellular vesicle uptake by microglia leads to increased microglial activation and improved uptake of Tau oligomers by microglia, suggesting that neural stem cell-derived small extracellular vesicles may prime microglia for a more effective immune response. These results support the hypothesis that neural stem cell-derived small extracellular vesicle-induced modulation of microglial function is crucial for preserving neuronal integrity and mitigating neurodegenerative processes. By elucidating the interactions between neural stem cell-derived small extracellular vesicles and microglia, our study opens new avenues for developing therapeutic strategies aimed at boosting microglial function and addressing neurodegenerative diseases such as Alzheimer's disease.
    Keywords:  Alzheimer’s disease; Tau oligomers; hippocampus; immune response; lysosomes; microglia; neural stem cells; neuroinflammation; single-nuclei RNA sequencing; small extracellular vesicles
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00195
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