The Gain-of-Function TREM2-T96K Mutation Increases Risk for Alzheimer’s Disease by Impairing Microglial Function [scRNA-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE307686 | GEO | 2025/09/17
REPOSITORIES: GEO
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Project description:The aim of this study is to characterize the underlying molecular mechanisms of the gain-of-function Trem2T96K mutation in Alzheimer’s disease (AD) pathogenesis by using the constitutive Trem2T96K knock-in mouse crossed to the 5xFAD mouse model of AD. Gene expression analyses were performed on microglial cells isolated from male and female Trem2+/+ (WT), 5xFAD;Trem2+/+, 5xFAD;Trem2T96K/+, and 5xFAD;Trem2T96K/T96K mice at 8 months of age to analyze the impact of the Trem2T96K mutation on the transcriptome of microglia in the setting of neuroinflammation (i.e. in the 5xFAD brain). The results revealed that Trem2T96K reprogrammed microglial gene expression and downregulated signaling pathways related to microglial function, specifically, in female 5xFAD mice.
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Project description: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.
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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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Project description:Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer’s Disease (AD) risk is associated with the TREM2R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here we tested whether TREM2 engagement by an agonistic mAb, hT2AB, designated as a surrogate ligand facilitates microglia responses in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant (TREM2CV) or TREM2R47H. scRNA-seq of microglia from TREM2CV-5XFAD mice treated once with control IgG exposed trajectories representative of activated microglial populations including disease-associated microglia (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia. All of these were underrepresented in TREM2R47H-5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia transitions. Moreover, Cyc-M and IFN-R microglia were better represented in female than male TREM2CV-5XFAD mice, likely reflecting a greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished the Cyc-M, IFN-R, and MHC-II pools in TREM2R47H-5XFAD mice. In TREM2CV-5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which microglia transitions in response to Aβ had already reached their peak. Repeated treatment with a murinized version mT2AB over a 10 days period increased brain content of chemokines in TREM2R47H-5XFAD mice, consistent with microglia expansion and shifts in gene expression patterns. Thus, the impact of hT2AB on microglia responses is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation.
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