Sleep disruption in the progression and treatment of Alzheimer's disease

阿尔茨海默病的进展和治疗中的睡眠中断

• 批准号: 10315098
• 负责人: Shenee Martin
• 金额: $ 3.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-03 至 2023-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315098
• 关键词: Acute; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animals; Anti-Inflammatory Agents; Appearance; Axon; Behavior; Behavioral; Biochemical; Biochemistry; Biological Assay; Brain; Chronic; Cognitive; Custom; Data; Deterioration; Development; Diagnosis; Disease; Disease Progression; Endocannabinoids; Ensure; Enzymes; Excessive Daytime Sleepiness; Female; Fractionation; Future; Genetic; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Inflammation; Institutionalization; Lead; Link; Lipase; Measures; Messenger RNA; Microtubule Stabilization; Molecular; Molecular Biology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurotransmitters; Onset of illness; Pathology; Patients; Pharmacology; Phenotype; Physiological; Polysomnography; Population; Prevalence; Proteins; Regulation; Role; Science; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; Sleep disturbances; Sleeplessness; Synapses; Synaptic Transmission; Testing; Therapeutic; Therapeutic Intervention; Training; Transgenic Mice; Western Blotting; age related; behavior test; cannabinoid receptor; career; cognitive function; cognitive testing; endocannabinoid signaling; endogenous cannabinoid system; excitotoxicity; expectation; experience; genetic manipulation; improved; mRNA Expression; male; mouse model; neuron loss; overexpression; prevent; sleep abnormalities; sleep behavior; sleep quality; sleep quantity; tau Proteins; tau aggregation; tau-1; therapeutic evaluation; therapeutic target; therapy design/development; training opportunity

Project Summary Sleep is an essential physiological behavior that supports cognitive function. In Alzheimer's disease (AD), a devastating neurodegenerative disorder, patients experience accelerated sleep loss which can be correlated with AD onset and contribute to AD progression. Tau is an axonal microtubule stabilizing protein that forms aggregates and contributes to the cognitive decline, synapse loss and neuronal death seen in AD. Recently, Tau has been shown to mislocalize and aggregate in synapses which may impair synapse weakening during sleep – likely responsible for forming the restorative benefits of sleep. Currently there are no therapies to alleviate the negative consequences of tau pathology in AD. Endocannabinoids provide an intriguing avenue for therapeutic intervention because of their role in promoting antinflammatory signaling and sleep. Therefore, the objectives of this proposal are to test the link between sleep disruption and tau aggregation and to test the therapeutic window targeting endocannabinoid signaling during sleep in advance of Tau pathology and cognitive decline. I hypothesize that sleep disruption occurs early in AD progression and is a major driver of subsequent tau mislocalization and aggregation, and cognitive decline. In order to test this hypothesis, I have obtained P301S (PS19) transgenic mice that overexpress aggregation-prone human Tau. These animals show age-dependent cognitive decline and Tau accumulation. In Aim 1, I will monitor sleep in 6 months PS19 and WT animals and correlate the appearance of sleep disruption with Tau pathology, in order to link sleep disruption and synaptic Tau pathology. Additionally, I will subject mice to chronic sleep disruption via a fragmented sleep paradigm to correlate sleep disruption with Tau pathology. Using various biochemical assays, I will identify sleep-dependent changes at the mRNA and protein level. In Aim 2 I will generate FAAH-/-/PS19 mice and define sleep phenotypes in males and females. I will determine whether genetic regulation of synaptic eCBs can improve sleep in PS19 mice and reduce tau pathology at 6 months. Additionally, I will test the lasting effects of genetic manipulation of eCBs on sleep quantity and quality through a battery of cognitive tests. Synaptic sleep-dependent changes will be identified through biochemical assays. These studies will provide a deeper understanding of the behavioral and molecular changes that occur during abnormal sleep in AD and highlight endocannabinoids as a suitable signaling pathway for enhancing the restorative benefits of sleep. This proposal combines behavior, biochemistry, pharmacology and molecular biology to provide outstanding training opportunities for my scientific development and future career in biomedical science.

项目总结