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

阿尔茨海默病小鼠模型睡眠碎片化的机制

• 批准号: 10662118
• 负责人: Luis De Lecea
• 金额: $ 190.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662118
• 关键词: Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Animals; Architecture; Arousal; Brain; Caregiver Burden; Caregivers; Caring; Cognition; Data; Dementia; Development; Disease; Disease Progression; Down-Regulation; Elderly; Electrophysiology (science); Fiber; Human; Hypothalamic structure; Impaired cognition; Impairment; Institution; Institutionalization; Intercellular Fluid; Intervention; Knock-in; Life; Link; Melatonin; Memory; Monitor; Mouse Protein; Mus; Neurons; Pathologic; Pattern; Persons; Photometry; Positioning Attribute; Potassium Channel; Property; Quality of life; REM Sleep; Regulation; Senile Plaques; Sleep; Sleep Architecture; Sleep Disorders; Sleep Fragmentations; Sleep Wake Cycle; Sleep disturbances; Slice; Synapses; Testing; Wakefulness; abeta accumulation; abeta deposition; aged; amyloid precursor protein processing; antagonist; cognitive function; design; experimental study; hypocretin; improved; improvement on sleep; mouse model; neuron loss; neuronal circuitry; neuronal excitability; non rapid eye movement; novel therapeutic intervention; optogenetics; pharmacologic; poor sleep; receptor; restoration; sleep abnormalities; sleep pattern; sleep quality; sleep regulation; synaptic failure; tau Proteins; translational potential; voltage

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.

阿尔茨海默病 (AD) 是老年人最具破坏性的疾病之一，其中睡眠障碍和 认知功能障碍通常需要机构护理。睡眠改变之间存在双向联系。 多位作者最近提出了一种新的模式和 AD 机制。 老年动物的睡眠碎片化涉及电压依赖性 KCNQ 钾的下调 产生促兴奋的下丘脑分泌素 (Hcrt) 的神经元中的通道也可能导致 Aβ 积累。 睡眠碎片，因为睡眠结构在淀粉样前体蛋白敲入 (APP-KI) 中被破坏 和 APP/PS1 AD 动物模型以及人类 AD 患者这些数据强烈表明存在因果关系。 AD 进展中涉及睡眠改变、Aβ 积累。 在此建议：i)；在 AD 和 AD 背景下监测促进唤醒的 Hcrt 和 LC 神经元的活动 确定 Aβ 是否改变切片记录中的内在特性；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； 确定药物或光遗传学睡眠增强是否会延迟 Aβ 积累并改善 两种 AD 小鼠模型的认知功能。拟议的针对唤醒的药理学实验。 回路具有很高的转化潜力，可以提高老年人的睡眠质量并减缓疾病进展 AD患者。