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Single cell genomic and epigenomic analysis of mouse and human Alzheimer's disease (Human)

ABSTRACT: Aging is the strongest risk factor for Alzheimer’s disease (AD), yet the mechanisms by which aging promotes AD progression remain incompletely understood. Chronic neuroinflammation is a hallmark of both brain aging and AD, with microglia undergoing progressive inflammatory and functional changes, but how these age-associated changes contribute to disease progression is unclear. Here, we profiled gene expression and chromatin accessibility in the hippocampus across aging and amyloid-β (Aβ) pathology, and identified progressive activation of cGAS-STING pathway and interferon-responsive microglial states that are markedly accelerated in the process. Pharmacological inhibition of STING in aged mice improved spatial memory, reduced Aβ plaque burden and shifted microglia from interferon-responsive states towards a phagocytic program associated with enhanced Aβ clearance. Mechanistically, STING activation reduced MEF2 activity and occupancy at enhancers of phagocytosis-associated genes, whereas STING inhibition restored MEF2 activity. Human AD hippocampal microglia similarly exhibited elevated IRF3 activity together with reduced MEF2C activity and nuclear availability. STING inhibition failed to preserve Aβ phagocytosis in MEF2C-deficient human iPSC-derived microglia. Together, these findings identify a cGAS–STING–MEF2 regulatory axis through which aging-associated innate immune signaling impairs microglial Aβ clearance and suggest that targeting cGAS–STING may restore protective microglial function in AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288063 | GEO | 2026/10/01

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE288063_RAW.tar	Raw
	GSE288063_ad13_filtered_feature_bc_matrix.h5	Other
	GSE288063_ad1551_filtered_feature_bc_matrix.h5	Other
	GSE288063_ad22rep1_filtered_feature_bc_matrix.h5	Other

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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.

Dataset Information

Single cell genomic and epigenomic analysis of mouse and human Alzheimer's disease (Human)

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