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Immune checkpoint molecule Tim-3 regulates microglial function and the development of Alzheimer’s disease pathology [scRNA-Seq]

ABSTRACT: Microglia, resident immune cells in the brain, play a critical role in neurodevelopment and neurological diseases. We investigated the role of the immune checkpoint molecule Tim-3 (Havcr2), which was recently identified as a genetic risk factor for late-onset Alzheimer’s disease (LOAD) in microglia. While Tim-3 has been shown to play an important role in inducing T cell exhaustion, it shows high and specific expression in the microglia where its role is unknown. Here we show that Tim-3 expression in microglia was induced by TGFβ signaling. Mechanistically, Tim-3 binds both Smad2 and Tgfbr2 by its C-terminus tail and enhances TGFβ signaling by promoting the phosphorylation of Smad2 by Tgfbr, thereby contributing to microglial homeostasis. Genetic deletion of Tim-3 in microglia resulted in increased phagocytic activity with a gene expression profile skewed towards neurodegenerative microglia (MGnD) phenotype, also known as disease-associated microglia (DAM). Moreover, microglia-targeted deletion of Tim-3 ameliorated AD pathology in 5xFAD mice. Single-nucleus RNA sequencing (snRNA-seq) identified a subpopulation among MGnD/DAM microglia in Havcr2-deficient 5xFAD mice, characterized by increased pro-phagocytic and anti-inflammatory gene expression together with decreased proinflammatory gene expression. Additional single-cell RNAseq confirmed these transcriptomic shifts in Havcr2-deficient 5xFAD mice in most microglial clusters. Our study shows a Tim-3-mediated regulatory mechanism of homeostatic microglia through its interaction with TGFβ signaling and the beneficial role of targeting microglial Tim-3 in AD mice. Our findings promise a potential therapeutic strategy targeting checkpoint molecule Tim-3 in currently intractable AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE267764 | GEO | 2025/01/13

REPOSITORIES: GEO

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Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.

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Immune checkpoint molecule Tim-3 regulates microglial function and the development of Alzheimer’s disease pathology [scRNA-Seq]

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