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.
Patients with Alzheimer?s Disease have disturbances of circadian rhythms, the 24-hour cycles that control bodily processes such as sleep and hormone secretion. We will use novel genetic techniques to identify all of the genes controlled by the circadian system in the mouse brain, and how these gene expression patterns are altered by aging or amyloid-beta plaque, as are seen in Alzheimer?s Disease.
| Lananna, Brian V; Nadarajah, Collin J; Izumo, Mariko et al. (2018) Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1. Cell Rep 25:1-9.e5 |
| Day, Gregory S; Musiek, Erik S; Morris, John C (2018) Rapidly Progressive Dementia in the Outpatient Clinic: More Than Prions. Alzheimer Dis Assoc Disord 32:291-297 |
