Project Summary/Abstract Alzheimer's disease is now considered by some experts to be the third leading cause of death in the United States, inflicting enormous health care and economic burdens on individuals, families and society. With advances in medical science and technology substantially extending human lifespan, the numbers of individuals living longer and affected by Alzheimer's disease and related dementias is expected to increase significantly. While sleep disturbances have long been viewed as symptoms of Alzheimer's disease and other neurodegenerative diseases, recent research has suggested that chronic sleep disruption may be a significant risk factor for Alzheimer's disease decades later. Poor sleep patterns and chronic sleep loss also appear to accelerate the rate of disease progression and pathogenesis. Acute and chronic sleep deprivation have also been shown to increase tau pathologies and amyloid beta peptides, pathological hallmarks of Alzheimer's disease. Recent estimates suggest that over 35% of adults suffer from chronic sleep deprivation making it imperative that we identify the mechanisms through which chronic sleep deprivation affects Alzheimer's pathogenesis. The hippocampus, a critical brain region for memory, is particularly susceptible to the effects of sleep deprivation and is one of the first regions to exhibit phenotypic pathologies in Alzheimer's disease. We hypothesize that chronic sleep deprivation causes aberrant nuclear RNA splicing and processing, and limits the available pool of mRNA for translation to affect gene expression in tau pathogenesis. The objective of this Alzheimer's disease Supplement proposal is to identify the impact of chronic sleep deprivation on neuronal mRNA processing in the nucleus and to define the translatome of excitatory neurons in the hippocampus in a mouse model of tauopathy related to Alzheimer's disease and related dementias. We will use deep neuronal nuclear RNA sequencing to identify the impact of chronic sleep deprivation on mRNA processing and splicing, and an advanced viral RiboTag strategy to specifically target excitatory neurons in the hippocampus followed by deep RNA sequencing of the mRNA associated with translating polyribosomes in a mouse model for tauopathies related to Alzheimer's disease. The results from our multi-level experiments defining genome-wide impacts of chronic sleep deprivation with cell-type specific resolution on RNA processing, and the identification of a cell-type specific translatome signature of chronic sleep deprivation, will provide significant insights into the negative impacts of sleep deprivation on tau pathogenesis related to Alzheimer's disease, potentially leading to the development of novel therapeutics to counteract the consequences of sleep loss on cognition and neurodegenerative disorders.