Alzheimer's Disease is one of the leading causes of death in the United States. With increases in longevity over the past fifty years, the numbers of individuals living longer and being affected by Alzheimer's Disease is expected to increase significantly over the next decade, imposing tremendous health care and economic burdens on individuals, families and society. Historically, sleep disorders and sleep disturbances have been viewed as symptoms of Alzheimer's Disease and other neurodegenerative diseases; however, recent research has implicated sleep deprivation or sleep disturbances as contributing factors to Alzheimer's Disease vulnerability and as a meaningful factor in the rate of disease progression and pathogenesis. In addition to contributing to the decline in memory and cognitive function, sleep deprivation has also been shown to increase tau pathologies and amyloid beta peptides, pathological hallmarks of Alzheimer's Disease. Given the dramatic rise in sleep deprivation across adults, teenagers and children over the past twenty years, it is imperative that we identify the mechanisms through which sleep deprivation affects Alzheimer's pathogenesis. The hippocampus, a critical brain region for memory, is particularly susceptible to the effects of acute sleep deprivation and is one of the first regions to exhibit phenotypic pathologies in Alzheimer's Disease. We hypothesize that sleep deprivation affects targets RNA splicing and processing, and 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 sleep deprivation on cell-type specific gene regulation and explicitly detail the pool of mRNA available for translation in a mouse model of tauopathy related to Alzheimer's disease before and after tau pathologies occur. We will use an advanced viral RiboTag strategy to specifically target excitatory neurons in the hippocampus followed by deep RNA sequencing of total RNA and the mRNA associated with translating polyribosomes. The results from our two stage experiments defining genome-wide interactions between sleep deprivation before the onset of tau pathologies and after development of tauopathies with cell-type specific resolution on RNA fate and protein synthesis, and the identification of cell-specific signatures of 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.
Sleep deprivation is a widespread public health problem impacting millions of Americans that has been implicated in the susceptibility and progression of Alzheimer's disease. The proposed studies will provide significant insight into changes in gene expression caused by sleep deprivation that may increase the susceptibility and progression of Alzheimer's disease through the investigation of changes in RNA regulation in a tauopathy mouse model. The results from the proposed research will lay the foundation for identification of novel targets and the development of future therapeutics to ameliorate the progression of pathologies in Alzheimer's disease and other neurodegenerative diseases.
