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

阿尔茨海默病(AD)是老年人最具破坏性的疾病之一，在这种疾病中，睡眠障碍和 认知功能障碍通常需要机构照顾。睡眠变化之间的双向联系 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 老年动物的睡眠碎片涉及电压依赖性KCNQ钾的下调 促进觉醒的下丘脑岛(Hcrt)产生神经元的通道。β的积累也可能有助于 由于两种淀粉样前体蛋白敲打蛋白(APP-KI)的睡眠结构被破坏，导致睡眠碎片化 以及APP/PS1 AD动物模型，以及人类AD患者。这些数据有力地表明了其中的因果关系 睡眠改变的参与，β在AD进展中的积累。 在此建议：i)；监测促进觉醒的Hcrt和LC神经元在AD和 确定β在切片记录中是否改变其固有属性；ii)确定β是否影响 NREM和REM睡眠活动神经元的活动及其维持睡眠结构的能力；iii) 确定药物或光遗传睡眠增强是否延缓和改善β积聚 两种阿尔茨海默病小鼠模型的认知功能。建议的针对唤醒的药理实验 回路具有很高的翻译潜力，可以提高老年人的睡眠质量，减缓老年人的疾病进展 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.