bims-microg 2025-04-13 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–04–13
thirty-two papers selected by
Marcus Karlstetter, Universität zu Köln

Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease.
Elucidating the Role of Trem2 in Lipid Metabolism and Neuroinflammation.
Microglia underlie amyloid-β clearance in immunized people with Alzheimer disease.
Microglia heterogeneity, modeling and cell-state annotation in development and neurodegeneration.
Nicotinamide Riboside Mitigates Retinal Degeneration by Suppressing Damaged DNA-Stimulated Microglial Activation and STING-Mediated Pyroptosis.
Expression of anti-amyloid CARs in microglia promotes efficient and selective phagocytosis of Aβ1‒42.
Mast cell promotes obesity by activating microglia in hypothalamus.
Liquid-liquid phase separation of RBM33 facilitates hippocampus aging by inducing microglial senescence by activating CDKN1A.
Evaluation of 5 Intermediate Structural Variations of Microglia Within an Organotypic Hippocampal Slice Model After Regionalized Toxic Injury.
Genetic risk for neurodegenerative conditions is linked to disease-specific microglial pathways.
Moss-derived human complement factor H modulates retinal immune response and attenuates retinal degeneration.
Potential roles for microglia in drug addiction: Adolescent neurodevelopment and beyond.
Spatial transcriptomics of the aging mouse brain reveals origins of inflammation in the white matter.
STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.
High-cellulose diet ameliorates cognitive impairment by modulating gut microbiota and metabolic pathways in mice.
Age-dependent glial heterogeneity and traumatic injury responses in a vertebrate brain structure.
Role of alpha-1 antitrypsin in Bruch's membrane integrity.
Myeloid lineage C3 induces reactive gliosis and neuronal stress during CNS inflammation.
Involvement of circadian clock protein PER2 in controlling sleep deprivation induced HMGB1 up-regulation by targeting p300 in the cortex.
Peripheral nervous system microglia-like cells regulate neuronal soma size throughout evolution.
Aerobic Exercise Restores Hippocampal Neurogenesis and Cognitive Function by Decreasing Microglia Inflammasome Formation Through Irisin/NLRP3 Pathway.
Microglial STING activation promotes neuroinflammation and pathological changes in experimental mice with intracerebral haemorrhage.
IFNγ preconditioning improves neuroprotection of MSC-derived vesicles on injured retinal ganglion cells by suppressing microglia activation via miRNA-dependent ribosome activity.
MgSO4 alleviates hippocampal neuroinflammation and BBB damage to resist CMS-induced depression.
LncRNA 4933431K23Rik modulate microglial phenotype via inhibiting miR-10a-5p in spinal cord injury induced neuropathic pain.
Male-Dominant Spinal Microglia Contribute to Neuropathic Pain by Producing CC-Chemokine Ligand 4 Following Peripheral Nerve Injury.
Unique N-glycosylation signatures in human iPSC derived microglia activated by Aβ oligomer and lipopolysaccharide.
Differential roles of the ADAM9/NF-κB and the ADAM9/STAT3 feedback loops in HIV-1 Tat-induced microglial inflammatory response and subsequent neuronal apoptosis.
Photobiomodulation modulates mitochondrial energy metabolism and ameliorates neurological damage in an APP/PS1 mousmodel of Alzheimer's disease.
CMPK2 promotes microglial activation through the cGAS-STING pathway in the neuroinflammatory mechanism.
The dual role of microglia in Alzheimer's disease: from immune regulation to pathological progression.
Inactivation of microglial LXRβ in early postnatal mice impairs microglia homeostasis and causes long-lasting cognitive dysfunction.

Nature. 2025 Apr 09.

Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease.

Kimitoshi Kimura, Ayshwarya Subramanian, Zhuoran Yin, Ahad Khalilnezhad, Yufan Wu, Danyang He, Karen O Dixon, Udbhav Kasyap Chitta, Xiaokai Ding, Niraj Adhikari, Isabell Guzchenko, Xiaoming Zhang, Ruihan Tang, Thomas Pertel, Samuel A Myers, Aastha Aastha, Masashi Nomura, Ghazaleh Eskandari-Sedighi, Vasundhara Singh, Lei Liu, Conner Lambden, Kilian L Kleemann, Neha Gupta, Jen-Li Barry, Ana Durao, Yiran Cheng, Sebastian Silveira, Huiyuan Zhang, Aamir Suhail, Toni Delorey, Orit Rozenblatt-Rosen, Gordon J Freeman, Dennis J Selkoe, Howard L Weiner, Mathew Blurton-Jones, Carlos Cruchaga, Aviv Regev, Mario L Suvà, Oleg Butovsky, Vijay K Kuchroo.

Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation1,2. This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer's disease3, and it can induce T cell exhaustion4. However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGFβ signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFβ signalling by promoting TGFBR-mediated SMAD2 phosphorylation, and this process maintains microglial homeostasis. Genetic deletion of Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype (MGnD), also referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-β pathology in 5×FAD mice (a transgenic model of Alzheimer's disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2-deficient 5×FAD mice characterized by increased pro-phagocytic and anti-inflammatory gene expression alongside reduced pro-inflammatory gene expression. These transcriptomic changes were corroborated by single-cell RNA sequencing data across most microglial clusters in Havcr2-deficient 5×FAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGFβ signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer's disease.

DOI: https://doi.org/10.1038/s41586-025-08852-z
CNS Neurosci Ther. 2025 Apr;31(4): e70338

Elucidating the Role of Trem2 in Lipid Metabolism and Neuroinflammation.

Chenhui Zhao, Wei Qi, Xiaoping Lv, Xueli Gao, Chaonan Liu, Shimin Zheng.

   BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and neuroinflammation. Astrocytes play a key role in the neuroinflammatory environment of AD, especially through lipid metabolism regulation. However, the mechanisms by which astrocytes, particularly through the triggering receptor expressed on myeloid cells 2 (Trem2) receptor, contribute to lipid dysregulation and neuroinflammation in AD remain inadequately understood.
METHODS: We employed an AD mouse model and integrated single-cell RNA sequencing (scRNA-seq), transcriptomics, and high-throughput metabolomics to analyze lipid metabolism and inflammatory profiles in astrocytes. Differential gene expression was further validated with the GEO database, and in vitro and in vivo experiments were conducted to assess the impact of Trem2 modulation on astrocytic inflammation and lipid composition.
RESULTS: Our findings demonstrate that Trem2 modulates lipid metabolism in astrocytes, affecting fatty acid and phospholipid pathways. In the AD model, Trem2 expression was suppressed, enhancing nuclear factor-κB (NF-κB) signaling and promoting the secretion of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Trem2 overexpression reduced astrocytic inflammation and altered lipid composition, attenuating neuroinflammation both in vitro and in vivo. These results underscore Trem2's regulatory role in lipid metabolism and its significant impact on neuroinflammation in AD.
CONCLUSIONS: This study identifies Trem2 as a pivotal regulator of astrocytic lipid metabolism and neuroinflammation in AD, providing potential molecular targets for early intervention and therapeutic strategies aimed at mitigating AD progression.

Keywords:  Alzheimer's disease; Trem2; astrocytes; lipid metabolism; neuroinflammation

DOI:  https://doi.org/10.1111/cns.70338
Nat Rev Neurol. 2025 Apr 10.

Microglia underlie amyloid-β clearance in immunized people with Alzheimer disease.

Lisa Kiani.

DOI: https://doi.org/10.1038/s41582-025-01084-9
Nat Neurosci. 2025 Apr 07.

Microglia heterogeneity, modeling and cell-state annotation in development and neurodegeneration.

Laura Fumagalli, Alma Nazlie Mohebiany, Jessie Premereur, Paula Polanco Miquel, Baukje Bijnens, Pieter Van de Walle, Nicola Fattorelli, Renzo Mancuso.

Within the CNS, microglia execute various functions associated with brain development, maintenance of homeostasis and elimination of pathogens and protein aggregates. This wide range of activities is closely associated with a plethora of cellular states, which may reciprocally influence or be influenced by their functional dynamics. Advancements in single-cell RNA sequencing have enabled a nuanced exploration of the intricate diversity of microglia, both in health and disease. Here, we review our current understanding of microglial transcriptional heterogeneity. We provide an overview of mouse and human microglial diversity encompassing aspects of development, neurodegeneration, sex and CNS regions. We offer an insight into state-of-the-art technologies and model systems that are poised to improve our understanding of microglial cell states and functions. We also provide suggestions and a tool to annotate microglial cell states on the basis of gene expression.

DOI: https://doi.org/10.1038/s41593-025-01931-4
Invest Ophthalmol Vis Sci. 2025 Apr 01. 66(4): 14

Nicotinamide Riboside Mitigates Retinal Degeneration by Suppressing Damaged DNA-Stimulated Microglial Activation and STING-Mediated Pyroptosis.

Shanshan Zhu, Lusi Zhang, Ping Tong, Jiawei Chen, Cong Wang, Zewei Wang, Jingyuan Liu, Peiyun Duan, Qian Jiang, Yubing Zhou, Guangshuang Tan, Xian Zhang, Bing Jiang.

Purpose: Microglial activation plays a pivotal role in the pathogenesis of retinal degeneration, contributing to neuroinflammation within the retina. Previous studies identified that nicotinamide riboside (NR) mitigated light-induced retinal degeneration (LIRD) and inhibited microglial activation. The cGAS-STING signaling pathway has been recognized as a key mediator of inflammation in response to cellular stress and tissue damage. This study further explores the regulatory impact of NR on microglial activation and STING-mediated pyroptosis in retinal degeneration.
Methods: Balb/c mice were subjected to bright light exposure to induce retinal degeneration. Bioinformatics analysis was used to identify the upregulated key genes and signaling pathways involved in the progression of retinal degeneration, based on mouse transcriptomes from the LIRD model. Molecular biology techniques and immunofluorescence staining were used to assess cGAS-STING activation and expression of pyroptosis-associated molecules. Retinal function, photoreceptor apoptosis and inflammatory response were evaluated in the presence and absence of NR supplementation.
Results: Exposure to bright light resulted in mitochondrial dysfunction and the release of dsDNA, significantly triggering the activation of cGAS-STING pathway and microglial pyroptosis. In contrast, NR treatment preserved mitochondrial biosynthesis, inhibited STING expression in reactive microglia, and dampened the pro-inflammatory response. Additionally, intraperitoneal administration of the STING inhibitor H151 reduced light-induced microglial activation and pyroptosis, while improving retinal function and promoting photoreceptor survival.
Conclusions: These findings suggest that NR confers neuroprotection by attenuating damaged DNA-triggered STING-mediated microglial activation and pyroptosis. Targeting the cGAS-STING pathway presents a promising therapeutic avenue for retinal degeneration.

DOI: https://doi.org/10.1167/iovs.66.4.14
Gene Ther. 2025 Apr 10.

Expression of anti-amyloid CARs in microglia promotes efficient and selective phagocytosis of Aβ1‒42.

Christina N Heiss, Rebecca Riise, Eric Hanse, Stefanie Fruhwürth, Henrik Zetterberg, Andreas Björefeldt.

Genetic engineering of microglial cells is a promising therapeutic avenue emerging with advancements in gene delivery techniques. Using a recently developed AAV capsid for efficient in vitro transduction we report the engineering of microglia with CARs (CAR-Mic) targeting phagocytosis of amyloid beta 1‒42 (Aβ42). Functional screening of seven CAR constructs in human iPSC-derived microglia revealed up to 6-fold increases in internalized Aβ relative to viral control. CAR-driven phagocytic enhancement was selective for Aβ, dependent on intracellular domain signaling, and was confirmed in primary mouse microglia. These findings highlight the potential of using this approach to target dysfunctional microglia in Alzheimer's disease and other CNS disorders.

DOI: https://doi.org/10.1038/s41434-025-00534-9
Front Endocrinol (Lausanne). 2025 ;16 1544213

Mast cell promotes obesity by activating microglia in hypothalamus.

Wen Tian, Jinghui Wang, Yangyang Zhu, Yi Zhang, Liwei Chen, Cheng Hu.

   Background: Obesity has become a significant public health issue, yet its underlying mechanisms remain complex. The hypothalamus, a crucial part of the central nervous system, plays a vital role in maintaining energy balance. Disruptions in hypothalamic homeostasis can lead to obesity and related metabolic disorders. Recent studies have increasingly focused on the role of intercellular interactions within the hypothalamus in obesity development, though the exact mechanisms are still under investigation. Mast cells, as innate immune cells, have been linked to obesity, but their specific roles and mechanisms require further exploration. This study aims to investigate whether hypothalamic mast cells influence microglia and subsequently affect metabolic homeostasis.
Methods: We conducted experiments to examine the effects of high-fat diets on mast cells in the arcuate nucleus of the hypothalamus. We analyzed the activation of microglia and the activity of POMC neurons in response to mast cell activation. The study involved feeding mice a high-fat diet and then assessing changes in mast cell populations, microglial activation, and neuronal activity in the hypothalamus.
Results: Our findings indicate that high-fat feeding increases the number of mast cells in the arcuate nucleus of the hypothalamus. These mast cells activate microglia, which in turn suppress the activity of POMC neurons. This suppression promotes appetite and reduces energy expenditure, leading to obesity. The results suggest a direct role of hypothalamic mast cells in the regulation of energy balance and obesity development.
Discussion: This study highlights the regulatory role of mast cells in the hypothalamus in the formation of obesity. By activating microglia and influencing POMC neuron activity, mast cells contribute to metabolic dysregulation. These findings provide a new target for the treatment of obesity and related metabolic diseases, emphasizing the importance of hypothalamic immune interactions in metabolic health. Further research is needed to explore the potential therapeutic applications of targeting mast cells in obesity management.

Keywords:  POMC neuron; diabetes; hypothalamus; mast cells; microglia; obesity

DOI:  https://doi.org/10.3389/fendo.2025.1544213
Int J Biol Macromol. 2025 Apr 09. pii: S0141-8130(25)03538-X. [Epub ahead of print] 142986

Liquid-liquid phase separation of RBM33 facilitates hippocampus aging by inducing microglial senescence by activating CDKN1A.

Xiaowen Yang, Lin Wei, Saifeng Zhong, Qiguang Wang, Yujun Zhang, Yonggang Zhang, Aiqing Yu.

  Microglia play an important role in hippocampus-dependent memory and cognitive function. Microglial aging contributes to hippocampal aging and influences neurodegenerative diseases, although the underlying mechanisms remain unclear. RBM33 was highly expressed in the hippocampus of naturally aged mice and senescent microglia. Hippocampus-specific genetic deletion of RBM33 alleviated age-related declines in learning and memory in aged RBM33 knockout (RBM33-/-) mice. In contrast, hippocampus-specific overexpression of RBM33 exacerbated these declines in aged RBM33 overexpression (RBM33Tg) mice, indicating that RBM33 acts as an age-promoting factor in the hippocampus. Mechanistically, RBM33 forms liquid-liquid phase separation (LLPS) both in vitro and in cells. RBM33 LLPS is required for its binding to the CDKN1A (p21cip1) promoter in a non-canonical transcriptional regulatory manner, leading to hippocampus-dependent declines in learning and memory by inducing microglial senescence. This study reveals that the RBM33 LLPS/ p21cip1 axis facilitates brain aging by inducing microglial senescence. Targeting the RBM33 LLPS/ p21cip1 axis may represent a therapeutic strategy to mitigate microglia senescence-mediated brain aging and hippocampus-dependent cognitive decline.

Keywords:  Hippocampus aging; Microglial senescence; RBM33

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142986
Cell Mol Neurobiol. 2025 Apr 09. 45(1): 34

Evaluation of 5 Intermediate Structural Variations of Microglia Within an Organotypic Hippocampal Slice Model After Regionalized Toxic Injury.

A Jesus Trejos, A X Francis Schanne.

  The dendritic cell of the CNS, the microglia (MG), is an initiation point of the immunological response within the post-blood-brain barrier (BBB) compartment. Microglia drastically changes in response to cell stress to a much different non-dendritic morphologies. This investigation postulates that if the first MG responses to toxic injury are isolated and studied in greater morphological detail, there is much to be learned about microglia's metamorphosis from and M2 to an M1 state. The organotypic hippocampal slice was the experimental setting used to investigate microglial response to toxic injury; this isolates dendritic cell to post-BBB cells dynamics from the impact of nonspecific of in vivo blood-derived signaling. Within the context of biochemically verified precise toxic cell injury/death (induced with mercury or cyanide in combination with 2-deoxy-glucose) to a specific region within the hippocampal slice, MG's morphological response was evaluated. There was up to 35% increase in microglia activation proximally to injury (CA3 region) and no changes distally (DG region) when compared to control slices treated with PBS. Maximum microglia activation consisted of a 3 plus-fold increase in the distance between the nucleus membrane and the cell membrane, which underscores an extensive and quantifiable amount of membrane rearrangement. This quantification can be applied to contemporaneous AI image analysis algorithms to demarcate and quantify relative MG activation in and around a site of injury. In between baseline and activated MG morphologies, 5 intermediate morphologies (or structural variations) are described as it relates to its cell body, nucleus, and dendrites. The result from this study reconciles details of MG's structure to its holistic characteristics in relation to parenchymal cell stress.

Keywords:   Inflammation; Toxicology; BBB; CD11; Dendritic cell; Interstitium/Intercellular space; Microglia

DOI:  https://doi.org/10.1007/s10571-025-01545-1
PLoS Genet. 2025 Apr 09. 21(4): e1011407

Genetic risk for neurodegenerative conditions is linked to disease-specific microglial pathways.

Aydan Askarova, Reuben M Yaa, Sarah J Marzi, Alexi Nott.

Genome-wide association studies have identified thousands of common variants associated with an increased risk of neurodegenerative disorders. However, the noncoding localization of these variants has made the assignment of target genes for brain cell types challenging. Genomic approaches that infer chromosomal 3D architecture can link noncoding risk variants and distal gene regulatory elements such as enhancers to gene promoters. By using enhancer-to-promoter interactome maps for human microglia, neurons, and oligodendrocytes, we identified cell-type-specific enrichment of genetic heritability for brain disorders through stratified linkage disequilibrium score regression. Our analysis suggests that genetic heritability for multiple neurodegenerative disorders is enriched at microglial chromatin contact sites, while schizophrenia heritability is predominantly enriched at chromatin contact sites in neurons followed by oligodendrocytes. Through Hi-C coupled multimarker analysis of genomic annotation (H-MAGMA), we identified disease risk genes for Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and schizophrenia. We found that disease-risk genes were overrepresented in microglia compared to other brain cell types across neurodegenerative conditions and within neurons for schizophrenia. Notably, the microglial risk genes and pathways identified were largely specific to each disease. Our findings reinforce microglia as an important, genetically informed cell type for therapeutic interventions in neurodegenerative conditions and highlight potentially targetable disease-relevant pathways.

DOI: https://doi.org/10.1371/journal.pgen.1011407
J Neuroinflammation. 2025 Apr 11. 22(1): 104

Moss-derived human complement factor H modulates retinal immune response and attenuates retinal degeneration.

Mandy Hector, Verena Behnke, Paulina Dabrowska-Schlepp, Andreas Busch, Andreas Schaaf, Thomas Langmann, Anne Wolf.

   BACKGROUND: AMD is a multifactorial progressive disease of the central retina that leads to severe vision loss among the elderly. Genome-wide association studies in AMD patients and preclinical data have identified a dysregulated complement system and aberrant microglia responses in the pathogenesis of AMD. Specifically, a genetic variant in the complement factor H (CFH) gene, an important inhibitor of the alternative complement pathway, confers the strongest risk for AMD. Here, we investigated whether moss-derived recombinant human CFH proteins, termed CPV-101 and CPV-104, can modulate microglia reactivity and limit retinal degeneration in a murine light damage paradigm mimicking important features of AMD.
METHODS: Two glycosylated human recombinant CFH proteins CPV101, and CPV-104 were produced in moss suspension cultures. In addition, glycans of the CPV-104 variant are sialylated, an optimization that makes CPV-104 an analog of human CFH. BALB/cJ mice received intravitreal injections of 5 µg CPV-101 and CPV-104 or vehicle, starting 1 day prior to exposure to 10,000 lx white light for 30 min. The effects of CPV-101 and CPV-104 treatment on mononuclear phagocyte and Müller cell reactivity were analyzed by immunostainings of retinal sections and flat mounts. Gene expression of microglia markers was analyzed using quantitative real-time PCR (qRT-PCR). Optical coherence tomography (OCT); Blue Peak Autofluorescence (BAF); terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and morphometric analyses were used to quantify the extent of retinal degeneration and photoreceptor apoptosis.
RESULTS: Light-exposed mice treated with moss-derived recombinant human full-length CFH showed reduced complement activation and MAC deposition in the retina. Concomitantly, mononuclear phagocyte and Müller cell reactivity in light-exposed retinas were also ameliorated upon CFH substitution. Moreover, attenuated light-induced retinal degeneration was detected in mice that received moss-derived CFH.
CONCLUSION: Modulating the alternative complement pathway using moss-derived recombinant human full-length CFH variant CPV-101 and CPV-104 counter-regulate gliosis and attenuates light-induced retinal degeneration, highlighting a promising concept for the treatment of AMD patients.

Keywords:  CPV-101; CPV-104; Complement factor H; Light damage; Microglia; Moss-derived recombinant CFH; Retinal degeneration

DOI:  https://doi.org/10.1186/s12974-025-03418-2
J Neuroimmunol. 2025 Mar 28. pii: S0165-5728(25)00080-3. [Epub ahead of print]404 578600

Potential roles for microglia in drug addiction: Adolescent neurodevelopment and beyond.

Maricela X Martinez, Stephen V Mahler.

  Adolescence is a sensitive period for development of addiction-relevant brain circuits, and it is also when people typically start experimenting with drugs. Unfortunately, such substance use may cause lasting impacts on the brain, and might increase vulnerability to later-life addictions. Microglia are the brain's immune cells, but their roles in shaping neural connectivity and synaptic plasticity, especially in developmental sensitive periods like adolescence, may also contribute to addiction-related phenomena. Here, we overview how drugs of abuse impact microglia, and propose that they may play poorly-understood, but important roles in addiction vulnerability and progression.

Keywords:  Addiction; Adolescence; Microglia; Neurodevelopment

DOI:  https://doi.org/10.1016/j.jneuroim.2025.578600
Nat Commun. 2025 Apr 04. 16(1): 3231

Spatial transcriptomics of the aging mouse brain reveals origins of inflammation in the white matter.

Lin Wang, Chang-Yi Cui, Christopher T Lee, Monica Bodogai, Na Yang, Changyou Shi, Mustafa O Irfanoglu, James R Occean, Sadia Afrin, Nishat Sarker, Ross A McDevitt, Elin Lehrmann, Shahroze Abbas, Nirad Banskota, Jinshui Fan, Supriyo De, Peter Rapp, Arya Biragyn, Dan Benjamini, Manolis Maragkakis, Payel Sen.

To systematically understand age-induced molecular changes, we performed spatial transcriptomics of young, middle-aged, and old mouse brains and identified seven transcriptionally distinct regions. All regions exhibited age-associated upregulation of inflammatory mRNAs and downregulation of mRNAs related to synaptic function. Notably, aging white matter fiber tracts showed the most prominent changes with pronounced effects in females. The inflammatory signatures indicated major ongoing events: microglia activation, astrogliosis, complement activation, and myeloid cell infiltration. Immunofluorescence and quantitative MRI analyses confirmed physical interaction of activated microglia with fiber tracts and concomitant reduction of myelin in old mice. In silico analyses identified potential transcription factors influencing these changes. Our study provides a resourceful dataset of spatially resolved transcriptomic features in the naturally aging murine brain encompassing three age groups and both sexes. The results link previous disjointed findings and provide a comprehensive overview of brain aging identifying fiber tracts as a focal point of inflammation.

DOI: https://doi.org/10.1038/s41467-025-58466-2
Mol Cell. 2025 Mar 27. pii: S1097-2765(25)00201-1. [Epub ahead of print]

STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.

Zhen Tang, Cong Xing, Antonina Araszkiewicz, Kun Yang, Wanwan Huai, Devon Jeltema, Nicole Dobbs, Yihe Zhang, Lu O Sun, Nan Yan.

  Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with diseases like lysosomal storage disorders (LSDs). How lysosomal defects are detected and lysosomal function restored remain incompletely understood. Here, we show that STING mediates a neuroinflammatory gene signature in three distinct LSD mouse models, Galctwi/twi, Ppt1-/-, and Cln7-/-. Transcriptomic analysis of Galctwi/twi mouse brain tissue revealed that STING also mediates the expression of lysosomal genes that are regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-sequencing (snRNA-seq) analysis show that STING regulates lysosomal gene expression in microglia. Mechanistically, we show that STING activation leads to TFEB dephosphorylation, nuclear translocation, and expression of lysosomal genes. This process requires STING's proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Furthermore, we show that the STING-TFEB axis facilitates lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control mechanism that responds to lysosomal dysfunction.

Keywords:  Krabbe disease; Niemann-Pick disease; STING; TFEB; innate immunity; lysosomal storage disorder; lysosome repair; neuroinflammation; non-canonical autophagy

DOI:  https://doi.org/10.1016/j.molcel.2025.03.008
J Nutr. 2025 Apr 09. pii: S0022-3166(25)00187-7. [Epub ahead of print]

High-cellulose diet ameliorates cognitive impairment by modulating gut microbiota and metabolic pathways in mice.

Moeka Tanabe, Kazuo Kunisawa, Imari Saito, Haruto Ojika, Kuniaki Saito, Toshitaka Nabeshima, Akihiro Mouri.

   BACKGROUND: Nutrition is a key factor in cognitive function, and safe dietary interventions are promising to prevent cognitive impairment in pediatric psychiatric disorders. We previously demonstrated that childhood social isolation (SI) stress affects colonic function, leading to cognitive impairment. Cellulose, an insoluble dietary fiber, shows benefits to intestinal health, but its potential impact on cognitive impairment has not been explored.
OBJECTIVES: This study investigated whether a high-cellulose diet ameliorates cognitive impairment induced by SI through modulation of gut microbiota and metabolic pathways.
METHODS: C57BL/6J male mice (3 weeks old; n=10-15/group) were randomly divided into two groups: individually housed (SI) group and housed five mice per cage (GH) group. Each group received either a normal diet (5% cellulose) or a high-cellulose diet (30% cellulose) for 5 weeks daily until the end of the behavioral testing. We evaluated behavior abnormalities, gut microbiota composition, and metabolites, and performed two-way ANOVA.
RESULTS: Intake of a high-cellulose diet ameliorated cognitive impairment, including decreased time spent in a novel location of SI mice in novel object location test (NOLT; +30%; p < 0.01) with reduction of Iba-1 positive cells, microglia, in the hippocampus (-33%; p < 0.05). The high-cellulose diet indicated significant difference in gut microbiota clustering plots (p < 0.01) and enhanced the variation in malate-aspartate shuttle pathways in SI mice (p < 0.01). Notably, fecal microbiota transplantation (FMT) from SI mice fed a high-cellulose diet after antibiotic treatment, replicated amelioration of cognitive impairment in NOLT (+46%; p < 0.01). Additionally, the FMT replicated a decrease of Iba-1 positive cells indicating suppressed hippocampal microglial activation (-52%; p < 0.01), and enhanced the variation in malate-aspartate shuttle pathways (p < 0.01).
CONCLUSIONS: These findings suggest that a high-cellulose diet may ameliorate pediatric-specific cognitive impairment through modulation of the gut microbiota and metabolic pathways.

Keywords:  cellulose; cognitive impairment; gut-brain axis; microglia; organic acids

DOI:  https://doi.org/10.1016/j.tjnut.2025.04.004
Cell Rep. 2025 Apr 07. pii: S2211-1247(25)00279-7. [Epub ahead of print]44(4): 115508

Age-dependent glial heterogeneity and traumatic injury responses in a vertebrate brain structure.

Huiwen Qin, Shuguang Yu, Ruyi Han, Jie He.

  The progression of traumatic brain injury (TBI) pathology is significantly influenced by age and involves a complex interplay of glial cells. However, the influence of age on the glial dynamics and their TBI responses remains mostly unexplored. Here, we obtain a comprehensive single-cell transcriptome atlas of three major glial types under the physiological and TBI conditions across four post-embryonic life stages in the zebrafish midbrain optic tectum. We identify a library of glial subtypes and states with specific age-dependent patterns that respond distinctly to TBI. Combining the glial interactome analysis and CRISPR-Cas9-mediated gene disruption, we reveal the essential roles of dla-notch3 and cxcl12a-cxcr4b interactions in the early-larval-stage-specific unresponsiveness of radial astrocytes to TBI and the TBI-induced age-independent recruitment of microglia to injury sites, respectively. Overall, our findings provide the molecular and cellular framework of TBI-induced age-related glial dynamics in vertebrate brains.

Keywords:  CP: Cell biology; CP: Neuroscience; age dependent; glial dynamics; microglia; oligodendrocyte-lineage cells; post-embryonic developmental stage; radial astrocytes; traumatic brain injury; zebrafish optic tectum

DOI:  https://doi.org/10.1016/j.celrep.2025.115508
Sci Rep. 2025 Apr 10. 15(1): 12223

Role of alpha-1 antitrypsin in Bruch's membrane integrity.

Shun-Yun Cheng, Delaney Giguere, Ilana Silverstein, Adrienne Conza, Johanna M Seddon, San Kim, Takeshi Iwata, Christian Mueller, Claudio Punzo.

  Alpha-1 antitrypsin (AAT) is a serine protease inhibitor that plays a crucial role in maintaining extracellular matrix integrity. Studies suggest that AAT augmentation therapy may benefit multiple eye diseases, including age-related macular degeneration (AMD). However, the function of endogenous AAT in the eye remains unclear. Here we used genetic knockout mice to study the role of AAT in eye health. We show that loss of AAT results in Bruch's membrane (BrM) thickening driven in part by increased laminin deposition with a concomitant decrease in collagen and elastin, which are two other critical BrM components. Interestingly, BrM remodeling due to excess extracellular protease activity reduced the age-related deposition at the BrM of apolipoprotein E, while increasing complement factor H and lowering secretion of the proangiogenic vascular endothelial growth factor. Despite these changes, the phagocytic function of the retinal pigment epithelium was not affected nor was the expression of genes that partake in photoreceptor cell metabolism. Consistent with loss of AAT resulting in changes that should alleviate AMD pathologies, human AMD donor eyes exhibited lower AAT expression levels in the BrM/choroid layer when compared to healthy donor eyes. Together, the study provides insight into AAT's function and its potential involvement in AMD.

Keywords:  A1AT; AAT; AMD risk alleles; Age-related macular degeneration; Alpha-1 antitrypsin; Bruch’s membrane

DOI:  https://doi.org/10.1038/s41598-025-96570-x
Nat Commun. 2025 Apr 12. 16(1): 3481

Myeloid lineage C3 induces reactive gliosis and neuronal stress during CNS inflammation.

Thomas Garton, Matthew D Smith, Ajay Kesharwani, Marjan Gharagozloo, Sungtaek Oh, Chan-Hyun Na, Martina Absinta, Daniel S Reich, Donald J Zack, Peter A Calabresi.

Complement component C3 mediates pathology in CNS neurodegenerative diseases. Here we use scRNAseq of sorted C3-reporter positive cells from mouse brain and optic nerve to characterize C3 producing glia in experimental autoimmune encephalomyelitis (EAE), a model in which peripheral immune cells infiltrate the CNS, causing reactive gliosis and neuro-axonal pathology. We find that C3 expression in the early inflammatory stage of EAE defines disease-associated glial subtypes characterized by increased expression of genes associated with mTOR activation and cell metabolism. This pro-inflammatory subtype is abrogated with genetic C3 depletion, a finding confirmed with proteomic analyses. In addition, early optic nerve axonal injury and retinal ganglion cell oxidative stress, but not loss of post-synaptic density protein 95, are ameliorated by selective deletion of C3 in myeloid cells. These data suggest that in addition to C3b opsonization of post synaptic proteins leading to neuronal demise, C3 activation is a contributor to reactive glia in the optic nerve.

DOI: https://doi.org/10.1038/s41467-025-58708-3
Sci Rep. 2025 Apr 10. 15(1): 12253

Involvement of circadian clock protein PER2 in controlling sleep deprivation induced HMGB1 up-regulation by targeting p300 in the cortex.

Min Zhang, Zhuoyao Ma, Haoran Cui, Yumeng Miao, Yu Yin, Qing Wen, Zhihui Liu, Xin Huang, Chen Xing, Kun Liu, Hui Peng, Lun Song.

  Lack of sleep is a common problem in current society, which can induce various brain dysfunctions. Neuroinflammation is a typical reaction caused by sleep deficit and is considered as a common basis for various neurological disorders and cognitive impairments, but the related mechanisms have not been fully clarified. The circadian clock protein plays a critical role in maintaining physiological homeostasis, including sleep/wake cycles. Circadian disorders induced by sleep deficit might contribute to the development of neuroinflammation. In the current study, we observed that sleep deprivation (SD) induced elevated expression of High-mobility group box 1 (HMGB1), one of the most important mediators of neuroinflammation, in the cortical microglia and cerebrospinal fluids. Moreover, acetylation-dependent nuclear export of HMGB1 was involved in up-regulation and secretion of HMGB1 after sleep deprivation. Further studies indicated that sleep deprivation induced an increase in the expression of acetyltransferase p300 and a decrease in the expression of deacetylase SIRT1, which synergistically enhanced the acetylation level of HMGB1 in the cortical microglial cells, thereby triggered the nuclear export and secretion of HMGB1. Most importantly, circadian clock protein PER2 constitutively interacted with p300 and inhibited its expression in the microglial cells, which can be interrupted by PER2 downregulation upon sleep deprivation, leading to the increased expression of p300 and acetylation and secretion of HMGB1. The truncated PER2 mutant without p300 binding ability lost its ability to regulate p300 expression, indicating that PER2 functioned as a co-suppressor of p300 in regulating acetylation and expression of HMGB1. Taken together, data in this study reveal a new mechanism by which PER2 is involved in controlling HMGB1 dependent neuroinflammation induced by sleep deprivation. Maintaining PER2 levels or blocking HMGB1 acetylation in the cortex might be prospective for preventing sleep deprivation-induced neuroinflammation and the related adverse reactions in the brain.

Keywords:  HMGB1; Neuroinflammation; PER2; Sleep deprivation; p300

DOI:  https://doi.org/10.1038/s41598-025-96931-6
Cell. 2025 Mar 25. pii: S0092-8674(25)00192-8. [Epub ahead of print]

Peripheral nervous system microglia-like cells regulate neuronal soma size throughout evolution.

Zhisheng Wu, Yiheng Wang, Wei-Wei Chen, Hua Sun, Xiaoyan Chen, Xiaobo Li, Zeshuai Wang, Weizheng Liang, Shuang-Yin Wang, Xuemei Luan, Yijiang Li, Shangjin Huang, Yuteng Liang, Jiaqi Zhang, Zhou-Feng Chen, Guanlin Wang, Yun Gao, Yanan Liu, Jun Wang, Zhen Liu, Peng Shi, Cirong Liu, Longbao Lv, Anli Hou, Chenglin Wu, Chen Yao, Zexuan Hong, Ji Dai, Zhonghua Lu, Fan Pan, Xin Chen, Helmut Kettenmann, Ido Amit, John R Speakman, Yun Chen, Florent Ginhoux, Rongfeng Cui, Tianwen Huang, Hanjie Li.

  Microglia, essential in the central nervous system (CNS), were historically considered absent from the peripheral nervous system (PNS). Here, we show a PNS-resident macrophage population that shares transcriptomic and epigenetic profiles as well as an ontogenetic trajectory with CNS microglia. This population (termed PNS microglia-like cells) enwraps the neuronal soma inside the satellite glial cell envelope, preferentially associates with larger neurons during PNS development, and is required for neuronal functions by regulating soma enlargement and axon growth. A phylogenetic survey of 24 vertebrates revealed an early origin of PNS microglia-like cells, whose presence is correlated with neuronal soma size (and body size) rather than evolutionary distance. Consistent with their requirement for soma enlargement, PNS microglia-like cells are maintained in vertebrates with large peripheral neuronal soma but absent when neurons evolve to have smaller soma. Our study thus reveals a PNS counterpart of CNS microglia that regulates neuronal soma size during both evolution and ontogeny.

Keywords:  PNS microglia; evolution; macrophage; microglia; microglia-like cell; microglial lineage; neuron development; neuronal soma size; peripheral microglia; peripheral nervous system

DOI:  https://doi.org/10.1016/j.cell.2025.02.007
Aging Cell. 2025 Apr 07. e70061

Aerobic Exercise Restores Hippocampal Neurogenesis and Cognitive Function by Decreasing Microglia Inflammasome Formation Through Irisin/NLRP3 Pathway.

Renqing Zhao, Xin Tian, Haocheng Xu, Yuanxin Wang, Junjie Lin, Bin Wang.

  Persistent microglial inflammation is a detrimental contributor to the progression of Parkinson disease (PD) pathology and related issues such as impaired adult hippocampal neurogenesis (AHN) and cognition. We conducted a 10-week exercise program with MPTP-treated mice to determine whether neuroinflammation can be addressed by aerobic exercise and elucidate its underlying regulatory mechanisms. Ten weeks of exercise significantly reduced PD-related pathology and enhanced AHN and memory. These changes were linked to a reduction in neuronal apoptosis, microglial inflammation, and NLRP3 inflammasome activation. In cultured microglia, fibril α-synuclein reduced FNDC5/irisin protein levels and induced NLRP3 inflammasome formation and IL-1β production, which could be diminished by recombinant irisin treatment. Interestingly, "runner serum" isolated from exercising rodents enhanced FNDC5/irisin expression and reduced NLRP3 inflammasome components and IL-1β secretion in α-synuclein-treated microglia. These effects could be diminished by blocking irisin signaling with cyclo RGDyk or NLRP3 agonist, nigericin sodium salt. Exercise-induced neuroprotective effects were weakened by treatment of MPTP-treated mice with cyclo RGDyk. In contrast, systematic administration of irisin partially replicated the beneficial effects of exercise on PD pathology, AHN, and memory function. As a nonpharmacological strategy, aerobic exercise effectively addresses PD pathology and preserves adult neurogenesis and cognition by mitigating microglial inflammation via mediating irisin/NLRP3 inflammasome pathways.

Keywords:  FNDC5/irisin; NLRP3 inflammasome; Parkinson disease; aerobic exercise; cognition; hippocampal neurogenesis

DOI:  https://doi.org/10.1111/acel.70061
Acta Pharmacol Sin. 2025 Apr 08.

Microglial STING activation promotes neuroinflammation and pathological changes in experimental mice with intracerebral haemorrhage.

Yu-Xiao Xue, Yi-Jun Chen, Mei-Zhen Qin, Fan-Fan Shang, Yi-Ting Lu, Yu-Hao Sun, Liu-Guan Bian, Ao Zhang, Yang Yu, Chun-Yong Ding.

  Neuroinflammation, a significant contributor to secondary brain injury, plays a critical role in the pathological process and prognosis of intracerebral haemorrhage (ICH). Thus, developing interventions to mitigate secondary neuroimmune deterioration is of paramount importance. Currently, no effective immunomodulatory drugs are available for ICH. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a recently identified innate immune-sensing pathway primarily expressed in microglia within the central nervous system (CNS) that has been implicated in the pathophysiology of various neurological diseases. In this study we investigated the role of cGAS-STING pathway in ICH. A collagenase model of ICH was established in mice. Brain tissues were collected on D1 or D3 post-ICH. We observed a significant increase in double-stranded (dsDNA) levels and activation of the cGAS-STING pathway in the perihaematomal region of ICH mice. Administration of a blood brain barrier-permeable STING antagonist H151 (10 mg/kg, i.p.) significantly decreased cell apoptosis, alleviated hematoma growth, and improved motor impairments in ICH mice, accompanied by inhibiting the STING pathway in microglia, reducing production/release of the cGAS-STING pathway downstream inflammatory factors, NLRP3 inflammasome activation and gasdermin D (GSDMD)-induced microglial pyroptosis. Microglial Sting conditional knockout significantly mitigated ICH-induced neuroinflammatory responses, pathological damage and motor dysfunction. These results suggest that the microglial STING pathway promotes brain pathological damage and behavioural defects in ICH mice by activating the NLRP3 inflammasome and microglial pyroptosis. The STING pathway may serve as a potential therapeutic target for ICH-induced secondary brain injury.

Keywords:  GSDMD; NLRP3; STING; intracerebral haemorrhage; neuroinflammation; pyroptosis

DOI:  https://doi.org/10.1038/s41401-025-01540-8
Extracell Vesicles Circ Nucl Acids. 2025 ;6(1): 87-111

IFNγ preconditioning improves neuroprotection of MSC-derived vesicles on injured retinal ganglion cells by suppressing microglia activation via miRNA-dependent ribosome activity.

Tianjing You, Yuanxing Yang, Luodan A, Xuan Cheng, Xi Lin, Qingle Liang, Lingling Ge, Jing Xie, Siyu Chen, Na Liu, Juncai He, Haiwei Xu, Xiang Ma.

  Aim: Microglial activation plays a pivotal role in the pathogenesis of retinal ganglion cell (RGC) degeneration resulting from optic nerve crush (ONC). Small extracellular vesicles (sEVs) secreted by mesenchymal stem cells (MSCs) have the potential to prevent retinal degeneration by modulating microglial activation. In this study, we elucidated the specific effects of sEVs derived from IFN-γ-primed MSCs on the phenotypic transition of microglia and the associated pathways in ONC mice. Methods: The ONC mice model was established and administered intravitreal injection with the sEVs derived from native MSCs (native sEVs) and the sEVs derived from MSCs primed with IFN-γ (IFNγ-sEVs). Their respective effects on the survival of the retinal ganglion cells (RGCs) and the transition of microglia phenotypes were determined through visual function testing and immunohistochemical staining. Combined with mRNA seq and microRNA seq techniques, we elucidated the mechanism of modulation of microglia phenotypic transformation by sEVs derived from MSCs primed by IFNγ. Results: It demonstrated that IFNγ-sEVs exhibited superior protective effects against RGC loss and reduced inflammatory responses in the ONC retina compared to native sEVs. Both types of sEVs promoted microglia activation to disease-associated microglia (DAM) phenotype, while IFNγ-sEVs especially suppressed interferon-responsive microglia (IRM) activation during RGCs degeneration. Subsequent miRNA sequencing suggested that miR-423-5p, which exhibited the most significant differential expression between the two sEVs types and elevated expression in IFNγ-sEVs, inhibited the expression of IRM and ribosomal genes. Conclusion: These findings suggest that IFN-γ-preconditioned MSCs may enhance sEVs of neuroprotection on RGCs by suppressing IRM activation through the secretion of sEVs containing specific microRNAs in ONC mice.

Keywords:  Optic nerve crush; interferon gamma; interferon-responsive microglia; microRNAs; ribosome activity; small extracellular vesicles

DOI:  https://doi.org/10.20517/evcna.2024.66
Front Nutr. 2025 ;12 1470505

MgSO4 alleviates hippocampal neuroinflammation and BBB damage to resist CMS-induced depression.

Qiaona Wang, Yuefeng Hu, Fan Li, Liyun Hu, Yizhu Zhang, Yunfa Qiao, Chuanfeng Tang, Renlei Wang.

   Purpose: Magnesium sulfate (MgSO4) possesses the advantages of being readily accessible, cost-effective, and having low toxicity. It has potential applications as a neuroprotective agent. The mechanisms underlying the effects of Mg2+ treatment on depression and its neuroprotective properties remain poorly elucidated.
Methods: In this study, we employed chronic mild unpredictable stress (CMS)-induced mice were orally administered with MgSO4 or pioglitazone. The CMS-induced depressive-like behaviors of mice were monitored. After sacrifice, the levels of Mg2+ and inflammatory cytokines were observed. Blood-brain barrier (BBB) permeability and the M1-to-M2 shift of microglia in mouse hippocampus were detected. The expression of proteins in IKK/NF-κB and NLRP3 inflammasome signal pathway were analyzed.
Results: We found that CMS induced depressive-like behaviors as well as hypomagnesemia in mice, which were accompanied with hypersecretion of inflammatory cytokines in hippocampus of mice. These animals induced by CMS exhibited hippocampal neuroinflammation characterized by an elevated number of Iba+ microglia with enlarged cell bodies and increased branching structures. In CMS-induced mice, MgSO4 alleviated CMS-induced depressive-like behaviors and hypomagnesemia, reduced the levels of inflammatory cytokines in both serum and hippocampus, decreased the number of Iba+ microglia, modulated microglia polarization and repaired the BBB damage. MgSO4 also significantly facilitates the M1-to-M2 shift in CMS-induced mouse hippocampus and lipopolysaccharide (LPS)-induced BV2 microglia. Mechanically, we found that MgSO4 inhibited microglia activation and BBB damage, possibly by suppressing IKK/NF-κB and NLRP3 inflammasome signaling pathways.
Conclusion: Our findings showed that MgSO4 supplementation played an active role in the prevention and treatment of depression.

Keywords:  CMS; MgSO4; blood-brain barrier; depression; hippocampal neuroinflammation

DOI:  https://doi.org/10.3389/fnut.2025.1470505
Sci Rep. 2025 Apr 04. 15(1): 11620

LncRNA 4933431K23Rik modulate microglial phenotype via inhibiting miR-10a-5p in spinal cord injury induced neuropathic pain.

Changhui You, Waiping Zhou, Ping Ye, Li Zhang, Wenchao Sun, Lili Tian, Bocheng Peng, Mengying Hu, Bo Xu.

  Neuropathic pain (NP) is caused by primary damage and dysfunction of nervous system, in which spinal cord injury (SCI) is a common cause of NP. Evidence shows that neuroinflammation and oxidative stress are related to the pathophysiology of NP, in which the activation of microglia and astrocytes in spinal is significant. Therefore, understanding the molecular mechanism of NP after SCI is of great significance. The rat model of SCI was established and BV2 cell was treated with LPS. The exosomes derived from astrocytes were extracted by centrifugation. The morphology of the exosomes was observed by electron microscope and the surface markers were detected by Western blot. LncRNA in astrocytes and astrocyte-derived exosomes were detected by qRT-PCR. The expression of microglia activation markers CD68 and Iba-1 was detected by immunohistochemistry. The von Frey test was applied to assess mechanical hypersensitivity. The heat plate analgesia instrument was used to evaluate Paw withdrawal latency (PWL). QRT-PCR used to detect expression of LncRNA49rik and miR-10a-5p. Western blot was used to detect MAPK/PI3K/AKT / mTOR signal pathway and COX2, iNOS. The content of MDA and the activity of SOD were detected by oxidative stress kit. The concentrations of IL-6, IL-1β, IL-18 and IFN-αwere detected by ELISA. The targeting relationship between LncRNA49rik and miR-10a-5p was analyzed by bioinformatics and double luciferase activity, Rip and FISH experiments. LncRNA49rik was highly expressed in astrocytes and its derived exosomes. SCI stimulated astrocytes to release exosome containing LncRNA49rik and promote microglia activation to increase inflammatory response. At the same time, overexpression of LncRNA49rik increased the incidence of NP and aggravated the level of inflammation and oxidative stress in rats with SCI. MiR-10a-5p is the target of LncRNA4933431K23Rik. Overexpression of LncRNA49rik significantly inhibited the up-regulation of miR-10a-5p. Overexpression of miR-10a-5p inhibited hyperalgesia and inflammation in SCI rats. In addition, transfection of miR-10a-5p mimics significantly inhibited the expression of MAPK/PI3K/AKT and up-regulated the expression of mTOR. Mechanism studies have shown that overexpression of miR-10a-5p weakens the phenotypic induction of microglia induced by LncRNA4933431K23Rik. LncRNA4933431K23Rik regulates microglial phenotype through inhibiting miR-10a-5p, which is responsible for NP induced by SCI.

Keywords:  Astrocytes; LncRNA4933431K23Rik; Neuropathic pain; Spinal cord injury; miR-10a-5p

DOI:  https://doi.org/10.1038/s41598-025-91021-z
Cells. 2025 Mar 23. pii: 484. [Epub ahead of print]14(7):

Male-Dominant Spinal Microglia Contribute to Neuropathic Pain by Producing CC-Chemokine Ligand 4 Following Peripheral Nerve Injury.

Fumihiro Saika, Tetsuya Sato, Takeru Nakabayashi, Yohji Fukazawa, Shinjiro Hino, Kentaro Suzuki, Norikazu Kiguchi.

  Recent studies have revealed marked sex differences in pathophysiological roles of spinal microglia in neuropathic pain, with microglia contributing to pain exacerbation exclusively in males. However, the characteristics of pain-enhancing microglia, which are more prominent in males, remain poorly understood. Here, we reanalyzed a previously published single-cell RNA sequencing dataset and identified a microglial subpopulation that significantly increases in the spinal dorsal horn (SDH) of male mice following peripheral nerve injury. CC-chemokine ligand 4 (CCL4) was highly expressed in this subpopulation and its mRNA levels were increased in the SDH after partial sciatic nerve ligation (PSL) only in male mice. Notably, CCL4 expression was reduced in male mice following microglial depletion, indicating that microglia are the primary source of CCL4. Intrathecal administration of maraviroc, an inhibitor of the CCL4-CC-chemokine receptor 5 (CCR5) signaling pathway, after PSL, significantly suppressed mechanical allodynia only in male mice. Furthermore, intrathecal administration of CCL4 induced mechanical allodynia in both sexes, accompanied by increased expression of c-fos, a neuronal excitation marker, in the SDH. These findings highlight a sex-biased difference in the gene expression profile of spinal microglia following peripheral nerve injury, with elevated CCL4 expression in male mice potentially contributing to pain exacerbation.

Keywords:  CCL4; CCR5; allodynia; female; inflammation; sex; spinal cord

DOI:  https://doi.org/10.3390/cells14070484
Sci Rep. 2025 Apr 10. 15(1): 12348

Unique N-glycosylation signatures in human iPSC derived microglia activated by Aβ oligomer and lipopolysaccharide.

Xinyu Tang, Ryan Lee Schindler, Jacopo Di Lucente, Armin Oloumi, Jennyfer Tena, Danielle Harvey, Carlito B Lebrilla, Angela M Zivkovic, Lee-Way Jin, Izumi Maezawa.

  Microglia are the immune cells in the central nervous system (CNS) and become pro-inflammatory/activated in Alzheimer's disease (AD). Cell surface glycosylation plays an important role in immune cells; however, the N-glycosylation and glycosphingolipid (GSL) signatures of activated microglia are poorly understood. Here, we study comprehensively combined transcriptomic and glycomic profiles using human induced pluripotent stem cells-derived microglia (hiMG). Distinct changes in N-glycosylation patterns in amyloid-β oligomer (AβO) and LPS-treated hiMG were observed. In AβO-treated cells, the relative abundance of bisecting N-acetylglucosamine (GlcNAc) N-glycans decreased, corresponding with a downregulation of MGAT3. The sialylation of N-glycans increased in response to AβO, accompanied by an upregulation of genes involved in N-glycan sialylation (ST3GAL4 and 6). Unlike AβO-induced hiMG, LPS-induced hiMG exhibited a decreased abundance of complex-type N-glycans, aligned with downregulation of mannosidase genes (MAN1A1, MAN2A2, and MAN1C1) and upregulation of ER degradation related-mannosidases (EDEM1-3). Fucosylation increased in LPS-induced hiMG, aligned with upregulated fucosyltransferase 4 (FUT4) and downregulated alpha-L-fucosidase 1 (FUCA1) gene expression, while sialofucosylation decreased, aligned with upregulated neuraminidase 4 (NEU4). Inhibition of sialylation and fucosylation in AβO- and LPS-induced hiMG alleviated pro-inflammatory responses. However, the GSL profile did not exhibit significant changes in response to AβO or LPS activation, at least in the 24-hour stimulation timeframe. AβO- and LPS- specific glycosylation changes could contribute to impaired microglia function, highlighting glycosylation pathways as potential therapeutic targets for AD.

Keywords:  Amyloid; Fucosylation; Glycosylation; Lipopolysaccharide; Microglia; Sialylation

DOI:  https://doi.org/10.1038/s41598-025-96596-1
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 07. pii: S0925-4439(25)00176-0. [Epub ahead of print] 167831

Differential roles of the ADAM9/NF-κB and the ADAM9/STAT3 feedback loops in HIV-1 Tat-induced microglial inflammatory response and subsequent neuronal apoptosis.

Xiaoting Qiao, Hongke Wei, Weixi Sun, Cailian Ruan, Duo Cao.

  ADAM has been implicated in causing several neurodegenerative diseases to progress. However, the precise function they play in HIV-associated neurocognitive disorders (HAND) remains incompletely elucidated. The HIV-1 transcriptional activator (Tat) has the capacity to evoke an inflammatory reaction within the microglia of the central nervous system. This, subsequently, initiates the apoptosis of neuronal cells. In the present research, our attention was centered on the part that ADAM9 plays in the microglia's response to Tat. We discovered that the stimulation with soluble Tat remarkably enhanced the manifestation of ADAM9 by means of the NF-κB and STAT3 pathway. In contrast, inhibition of ADAM9 significantly reduced Tat-triggered NF-κB and STAT3 signaling. Moreover, both ADAM9/NF-κB and ADAM9/STAT3 feedback loops exacerbated Tat-induced microglia inflammatory responses. However, further studies showed that the ADAM9/NF-κB feedback loop more significantly promoted neuronal apoptosis mediated by conditioned medium secreted by microglia after Tat stimulation. This study offers a novel perspective on the function of diverse feedback circuits in the etiopathogenesis of HAND. It can be posited that, when considered as a collective entity, ADAM9 may represent a viable candidate for therapeutic intervention in the context of preventing neuronal injury associated with HAND by modulating the inflammatory response of microglia and influencing neuronal injury.

Keywords:  ADAM9; HIV-associated neurocognitive disorder; NF-κB; Neuroinflammation; STAT3; Tat

DOI:  https://doi.org/10.1016/j.bbadis.2025.167831
Alzheimers Res Ther. 2025 Apr 05. 17(1): 72

Photobiomodulation modulates mitochondrial energy metabolism and ameliorates neurological damage in an APP/PS1 mousmodel of Alzheimer's disease.

Hongli Chen, Na Li, Na Liu, Hongyu Zhu, Chunyan Ma, Yutong Ye, Xinyu Shi, Guoshuai Luo, Xiaoxi Dong, Tao Tan, Xunbin Wei, Huijuan Yin.

   BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease. Amyloid β-protein (Aβ) is one of the key pathological features of AD, which is cytotoxic and can damage neurons, thereby causing cognitive dysfunction. Photobiomodulation (PBM) is a non-invasive physical therapy that induces changes in the intrinsic mechanisms of cells and tissues through low-power light exposure. Although PBM has been employed in the treatment of AD, the effect and precise mechanism of PBM on AD-induced neurological damage are still unclear.
METHODS: In vivo experiments, PBM (808 nm, 20 mW/cm2) was used to continuously interfere with APP/PS1 mice for 6 weeks, and then their cognitive function and AD pathological changes were evaluated. In vitro experiments, lipopolysaccharide (LPS) was used to induce microglia to model inflammation, and the effect of PBM treatment on microglia polarization status and phagocytic Aβ ability was evaluated. Hexokinase 2 (HK2) inhibitor 3-bromopyruvate (3BP) was used to study the effect of PBM treatment on mitochondrial energy metabolism in microglia.
RESULTS: PBM further ameliorates AD-induced cognitive impairment by alleviating neuroinflammation and neuronal apoptosis, thereby attenuating nerve damage. In addition, PBM can also reduce neuroinflammation by promoting microglial anti-inflammatory phenotypic polarization; Promotes Aβ clearance by enhancing the ability of microglia to engulf Aβ. Among them, PBM regulates microglial polarization and inhibits neuronal apoptosis, which may be related to its regulation of mitochondrial energy metabolism, promotion of oxidative phosphorylation, and inhibition of glycolysis.
CONCLUSION: PBM regulates neuroinflammatory response and inhibits neuronal apoptosis, thereby repairing Aβ-induced neuronal damage and cognitive dysfunction. Mitochondrial energy metabolism plays an important role in PBM in improving nerve injury in AD mice. This study provides theoretical support for the subsequent application of PBM in the treatment of AD.

Keywords:  Alzheimer’s disease; Apoptosis; Microglia; Mitochondrial energy metabolism; Photobiomodulation

DOI:  https://doi.org/10.1186/s13195-025-01714-w
Sci Rep. 2025 Apr 07. 15(1): 11807

CMPK2 promotes microglial activation through the cGAS-STING pathway in the neuroinflammatory mechanism.

Feng Gao, Zijian Zheng, Xinjie Liu, Jianwei Li.

  The activation of microglia and the resulting neuroinflammation play crucial regulatory roles in the pathogenesis and progression of neurological diseases, although the specific mechanisms remain incompletely understood. Cytidine monophosphate kinase 2 (CMPK2) is a key mitochondrial nucleotide kinase involved in cellular energy metabolism and nucleotide synthesis. Recent studies suggest that CMPK2 plays a role in microglial-mediated neuroinflammation; however, its specific impact on microglial activation remains unclear. In this study, we hypothesize that CMPK2 promotes microglial-mediated neuroinflammation by activating the cGAS-STING signaling pathway. To investigate this mechanism, we employed lipopolysaccharide (LPS)-treated microglial cells to investigate the detailed mechanisms by which CMPK2 regulates neuroinflammation. Our experimental results indicate that in the BV2 and mouse primary microglial neuroinflammation model, both CMPK2 protein and transcript levels were significantly elevated, accompanied by microglial activation phenotypes such as increased cell size, shortened processes, transformation to round or rod-like shapes, and elevated CD40 expression. Concurrently, there was an increase in pro-inflammatory cytokine levels and a decrease in anti-inflammatory cytokine levels. Further investigation revealed that in the microglial, the expression of cGAS and STING was elevated, along with an increase in oxidative products and inflammatory responses. CMA stimulation further intensified these changes, while cGAS knockdown mitigated them. Finally, we demonstrated that cGAS knockdown inhibited the oxidative stress, cell activation-related changes, and neuroinflammatory responses induced by CMPK2 overexpression in the BV2 neuroinflammation model. Molecular docking experiments showed that CMPK2 stably binds to cGAS at the protein level. These findings suggest that the cGAS-STING pathway mediates CMPK2-induced microglial activation. In summary, our study demonstrates that LPS-induced CMPK2 overactivity promotes microglial activation and neuroinflammatory through the cGAS-STING pathway.

Keywords:  CMPK2; Microglia; Neuroinflammatory; cGAS-STING Pathway

DOI:  https://doi.org/10.1038/s41598-025-97232-8
Front Aging Neurosci. 2025 ;17 1554398

The dual role of microglia in Alzheimer's disease: from immune regulation to pathological progression.

Cong He, Baojiang Chen, Hecai Yang, Xiaoqing Zhou.

  Alzheimer's disease (AD) is a widespread neurodegenerative disorder and one of the major challenges for public health. Despite extensive research, the role of microglia in AD remains complex and dual. The aim of this review is to summarize the most recent advances in research regarding the dual role of microglia in AD concerning both immunomodulation and pathological progression by considering mechanisms of activation of microglia, effects on Aβ clearance, tau pathology, and impacts due to genetic variations on microglial functions. Among these findings are the dual role of microglia, the status of activation for M1 and M2 phenotypes, and the crucial role that genetic variants like TREM2 have in modulating the response of microglia. This review describes how modulation of the microglial signaling pathway might be exploited therapeutically for AD treatment and underlines the relevance of a personalized medicine approach.

Keywords:  Alzheimer’s disease; amyloid-beta clearance; genetic variants; microglia; neuroinflammation

DOI:  https://doi.org/10.3389/fnagi.2025.1554398
Proc Natl Acad Sci U S A. 2025 Apr 15. 122(15): e2410698122

Inactivation of microglial LXRβ in early postnatal mice impairs microglia homeostasis and causes long-lasting cognitive dysfunction.

Keyi Lv, Yi Luo, Tianyao Liu, Meiling Xia, Hong Gong, Dandan Zhang, Xuan Chen, Xin Jiang, Yulong Liu, Jiayin Liu, Yulong Cai, Per Antonson, Margaret Warner, Haiwei Xu, Jan-Åke Gustafsson, Xiaotang Fan.

  Microglia, the largest population of brain immune cells, play an essential role in regulating neuroinflammation by removing foreign materials and debris and in cognition by pruning synapses. Since liver X receptor β (LXRβ) has been identified as a regulator of microglial homeostasis, this study examined whether its removal from microglia affects neuroinflammation and cognitive function. We used a cell-specific tamoxifen-inducible Cre-loxP-mediated recombination to remove LXRβ from microglia specifically. We now report that ablation of LXRβ in microglia in early postnatal life led to a reduction in microglial numbers, distinct morphological changes indicative of microglial activation, and enhanced synapse engulfment accompanied by cognitive deficits. Removal of LXRβ from microglia in adult mice caused no cognitive defects. RNAseq analysis of microglia revealed that loss of LXRβ led to reduced expression of SAll1, a master regulator of microglial homeostasis, while increasing expression of genes associated with microglial activation and CNS disease. This study demonstrates distinctly different functions of microglial LXRβ in developing and adult mice and points to long-term consequences of defective LXRβ signaling in microglia in early life.

Keywords:  LXRβ; cognitive function; microglia; microglia homeostasis; synapse engulfment

DOI:  https://doi.org/10.1073/pnas.2410698122