Characterization of premature cell senescence in Alzheimer’s disease using single nuclear transcriptomics
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ABSTRACT: Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in post mortem brains from non-diseased controls (NDC) and donors with Alzheimer’s disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (>200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (>4-fold) and p16INK4A (up to 2-fold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater -amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for -amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.
ORGANISM(S): Homo sapiens
PROVIDER: GSE264648 | GEO | 2024/04/26
REPOSITORIES: GEO
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