Role of Glial Circadian Clock Dysfunction in the Pathogenesis of Alzheimer's Disease

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Project Summary This project is a supplement to R01AG054517, “Role of Glial Circadian Clock Dysfunction in the Pathogenesis of Alzheimer’s Disease“. Circadian rhythm dysfunction is a critical component of Alzheimer’s Disease (AD), though its impact on disease pathogenesis is not fully understood. We have shown that disrupting circadian rhythms in mice can causes glial cell activation, inflammation, and accelerate amyloid plaque pathology, though the mechanisms underlying these phenomena are not fully understood. In this supplement application, we propose to use a new technology, single-nucleus RNA sequencing (snRNA-seq), to elucidate the circadian transcriptomes of all cell types in the brain. We will also examine these cell-type-specific circadian transcriptomes in aged mice, and in a mouse mode of amyloid plaque deposition (APPPS1-21 mice), in order to determine how AD-related pathology can impact circadian transcription in different cell types in the brain. These studies will generate a definitive database of circadian transcription in most cell types in the brain, as well as changes which occur in aging and amyloidosis. This dataset will provide valuable insights into how the circadian systems influence glial and neuronal function, how this is perturbed in AD, and what pathways may represent new therapeutic targets for intervention.