This application is submitted in response to NOT-AG-20-008 Alzheimer's-focused administrative supplements as a supplement to P40-OD010965 the Vervet Research Colony as a Biomedical Resource (VRC). The VRC is a national biomedical research resource mandated to provide the research community with access to pedigreed, genomically-sequenced, pathogen-free Caribbean-origin vervets/African green monkeys (Chlorocebus aethiops sabaeus). Vervets are increasingly recognized as a valuable NHP model for Alzheimer?s disease (AD). Vervets have age-related brain changes similar to humans including increases in A? plaque burden, cognitive and motor deficits, and changes in CSF AD biomarkers and changes with age in cortical transcription profiles. Also like humans, greater plaque and paired helical filament tau (phf-tau) burden are associated with reductions in brain volumes and cerebral glucose utilization. Like humans, some vervets develop insulin resistance with age that may progress to type 2 diabetes accompanied by decreased CSF A?42/A?40. Age-related sleep, and sleep?related cognitive function have not been studied in vervets and there are only two reports in other NHPs. In humans, poor sleep impairs cognitive functioning. While quantity and quality of sleep decline with age, these decrements are exaggerated in AD. Poor sleep and daytime somnolence are associated with greater AD neuropathology as indicated by CSF and neuroimaging biomarkers. Prospective studies suggest that poor sleep increases subsequent risk of AD. However, in mice, A? plaque deteriorates the sleep-wake cycle suggesting that A? and sleep may have a bidirectional relationship. Sleep disturbances are associated with insulin resistance, and increase risk for type 2 diabetes. Peripheral insulin resistance increases risk for cognitive impairment and AD. However, type 2 diabetics have poor sleep suggesting these relationships also may be bidirectional. Determination of age-related changes in sleep, and their relationships with cognitive performance, insulin resistance, and AD risk may lead to new targets for therapeutic intervention. Our overall goal is to develop the vervet as a model in which to identify novel targets and evaluate therapies for the detrimental effects of poor sleep on cognitive function, insulin resistance, and AD-like neuropathology.
Our specific aims are to determine, in middle-aged and elder vervets, age differences in sleep quantity and quality, and whether poor sleep is associated with poor cognitive function, AD neuroimaging and CSF biomarkers, or insulin resistance, and if age mediates these relationships. The results of this study will provide a NHP model and pilot data to support subsequent applications to determine the temporal order of emergence of these disorders in a longitudinal study, whether therapeutic intervention on sleep improves cognitive and metabolic function, and CSF and neuroimaging biomarkers, and identify novel therapeutic targets to intervene on the detrimental effects of poor sleep on cognitive function, insulin resistance, and AD-like neuropathology.
The proposed study will determine if nonhuman primates have aging related sleep decrements, and whether poor sleep is associated with poor cognitive function, insulin resistance, and Alzheimer?s disease risk. The study will provide a NHP model and pilot data to support future applications to determine the temporal order of emergence of these disorders in a longitudinal study, whether therapeutic intervention on sleep improves cognitive and metabolic function, and mitigate Alzheimer?s disease risk, and identify novel therapeutic targets to intervene on the detrimental effects of poor sleep on cognitive function, insulin resistance, and AD-like neuropathology.
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