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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

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项目摘要

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.

阿尔茨海默氏病（AD）是老年人中最具破坏性的疾病之一，睡眠障碍和认知功能障碍通常需要机构护理。睡眠改变之间的双向联系模式和广告已由多位作者提出。我们最近确定了一种新机制老年动物的睡眠碎片化涉及电压依赖性KCNQ钾的下调产生的神经元中唤醒促进性低封素（HCRT）中的通道。 Aβ的积累也可能有助于睡眠碎片化，因为在淀粉样蛋白蛋白敲击蛋白（APP-KI）中，睡眠结构被破坏 AD的APP/PS1动物模型以及人类AD患者。这些数据强烈建议因果关系睡眠改变的参与，Aβ积累在AD的进展中。在这里提出的建议：i）;在AD和确定Aβ是否在切片记录中改变其内在特性； 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； iii）确定药理学或光学睡眠增强是否会延迟Aβ的积累并改善 AD的两个鼠标模型中的认知功能。提出的针对唤醒的药物实验电路具有很高的翻译潜力，可以提高古老而缓慢的疾病进展中的睡眠质量广告患者。