Mechanisms of sleep fragmentation in a mouse model of Alzheimer's disease

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Alzheimer’s Disease (AD) is one of the most devastating diseases in older adults, in which sleep disorders and cognitive function impairments usually require institutional care. A bidirectional link between alterations in sleep patterns and AD has been proposed by multiple authors. We have recently identified a new mechanism of sleep fragmentation in aged animals that involves downregulation of voltage-dependent KCNQ potassium channels in arousal-promoting hypocretin (Hcrt)-producing neurons. Aβ accumulation may also contribute to sleep fragmentation since sleep architecture is disrupted in both amyloid precursor protein knockin (APP-KI) and APP/PS1 animal models of AD, as well as human AD patients. These data strongly suggest a causal involvement of sleep alterations, Aβ accumulation in the progression of AD. Here propose to: i);monitor the activity of wake-promoting Hcrt and LC neurons in the context of AD and determine whether Aβ changes their intrinsic properties in slice recordings; ii) determine whether Aβ affects the activity of NREM and REM sleep-active neurons and their ability to maintain sleep archtecture; iii) determine whether pharmacological or optogenetic sleep enhancement delays Aβ accumulation and improves cognitive function in two mouse models of AD. The proposed pharmacological experiments targeting arousal circuits have high translational potential to increase sleep quality in the elderly and slow disease progression in AD patients.