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

阿尔茨海默病（AD）是老年人中最具破坏性的疾病之一，其中睡眠障碍和 认知功能受损通常需要机构护理。睡眠改变之间的双向联系 模式和AD已经由多个作者提出。我们最近发现了一种新的机制， 涉及电压依赖性KCNQ钾下调的老年动物睡眠片段化 通道的觉醒促进下丘脑泌素（Hcrt）产生的神经元。Aβ蓄积也可能导致 睡眠片段化，因为睡眠结构在淀粉样前体蛋白敲入（APP-KI） 和AD的APP/PS1动物模型以及人类AD患者。这些数据有力地表明， AD进展中的睡眠改变、Aβ蓄积的参与。 这里提出：i）;监测AD背景下促进唤醒的Hcrt和LC神经元的活性， 确定Aβ是否改变切片记录中的固有特性; ii）确定Aβ是否影响 NREM和REM睡眠活跃神经元的活动及其维持睡眠结构的能力; iii） 确定药理学或光遗传学睡眠增强是否延迟Aβ积累并改善A β水平。 两种AD小鼠模型的认知功能。针对唤醒的药理学实验 神经回路具有很高的转化潜力，可以提高老年人的睡眠质量， AD患者。

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.