Sleep abnormalities in Down Syndrome-related Alzheimer's disease

唐氏综合症相关阿尔茨海默病的睡眠异常

• 批准号: 10658057
• 负责人: CHARLES A HOEFFER
• 金额: $ 70.07万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658057
• 关键词: ARNTL gene; Address; Affect; Age; Age of Onset; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid Beta A4 Precursor Protein; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Articulation; Basic Science; Behavior; Behavior assessment; Biochemical; Biological Assay; Brain; Calcineurin; Cell model; Chromosome 21; Chronic; Circadian Dysregulation; Clinical; Cognition; Cognitive; Cognitive deficits; Data; Defect; Development; Disease; Disease Progression; Dose; Down Syndrome; Early Onset Alzheimer Disease; Electroencephalography; Electrophysiology (science); Evaluation; Gene Dosage; Gene Expression; Gene Expression Profile; Genes; Goals; Grant; Health; Hippocampus; Human; Impaired cognition; Impairment; Individual; Induced pluripotent stem cell derived neurons; Knowledge; Link; Measurement; Measures; Mediator; Methods; Mission; Mitochondria; Modeling; Molecular; Mus; Nerve Degeneration; Neurobiology; Neurologic Deficit; Neurons; Outcome; Outcome Measure; Pathologic; Pathology; Phenotype; Process; Property; Protein Isoforms; Protein Overexpression; Proteins; Publishing; Quality of life; Research; Role; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Time; Trisomy; United States National Institutes of Health; Work; age related; aged; awake; calcineurin phosphatase; circadian; circadian pacemaker; cytokine; early onset; experimental study; gene correction; genetic manipulation; glial activation; high reward; high risk; immune activation; improvement on sleep; innovation; insight; mouse Ts65Dn; mouse model; multi-electrode arrays; neural; neuroinflammation; neuropathology; non rapid eye movement; overexpression; restoration; sleep abnormalities; sleep quality; tau Proteins; theories; transcriptome

PROJECT ABSTRACT The NIH INCLUDE initiative focuses on critical health and quality-of-life needs for individuals with Down syndrome (DS). Part of this mission is “to conduct targeted, high-risk, high-reward basic science studies on chromosome 21.” In addition, the NIA is prioritizing research that aims “to understand the molecular mechanism(s) underlying the interplay between aging and neurodegeneration in DS”. This proposal addresses these goals by DS-AD links in sleep disturbances in DS individuals. Connections between Alzheimer’s disease (AD) and DS are well-documented, but the mechanisms underlying them are little understood. A strong candidate is the cleavage product of Amyloid Precursor Protein (APP), Aβ, a defining histopathological marker of AD which promotes sleep dysfunction. Another candidate trisomy21 gene, Regulator of Calcineurin1 (RCAN1), affects circadian function and promotes AD-related pathology. This proposal focuses on APP and RCAN1 overexpression as mechanistic links between DS and AD-related disease involved in sleep disruption, circadian dysregulation, cognition impairment, and synaptic deficits. Our preliminary data demonstrate that genetic manipulation to restore Rcan1 to normal levels rescues sleep disturbances in a DS model. Therefore, our central hypothesis is that RCAN1 triplication in DS promotes sleep disturbances and exacerbates AD- related pathology. However, because APP and Aβ42 disrupt sleep and induce cognitive deficits, we will also assess the role of APP overexpression in DS sleep disturbances. Specifically, we will: 1) determine the effects of App and Rcan1 gene dosage correction on age-dependent sleep disruption and circadian clock expression in DS model mice; 2) quantify the effects of Rcan1 gene dosage correction on age-dependent synaptic deficits and network firing properties in DS model neurons; and 3) leverage the power of transcriptome analyses to infer molecular mechanisms underlying sleep disruption in Dp16 mice. Outcome measures for the proposal include sleep and circadian behavioral assessments; hippocampal slice electrophysiology; multi-electrode array (MEA) recordings in DS-derived neuronal culture; unbiased transcriptome analyses; cytokine protein assays; and immunohistochemical evaluation of glial activation and pathological tau. Our approach is conceptually and technically innovative because the role of APP and/or RCAN1 have not been formally considered in DS-AD-linked sleep abnormalities. Also, MEA methods not been used to study sleep in a DS model. This study is significant because, despite the links we have articulated, the role of APP or RCAN1 overexpression in promoting DS-related sleep or cognitive abnormalities has not been investigated. Data from the successful completion of this project will begin to fill a critical knowledge gap by determining how APP/RCAN1expression influences sleep disturbances and progression of AD-like pathology in DS. Importantly, data implicating APP/RCAN1-induced neuroinflammatory processes would suggest potential therapeutic avenues that could improve sleep quality or slow disease progression in DS individuals.

项目摘要 NIH INCLUDE计划关注唐氏症患者的关键健康和生活质量需求 综合症（DS）。这一使命的一部分是“进行有针对性的、高风险的、高回报的基础科学研究， 21号染色体”此外，NIA正在优先考虑旨在“了解分子生物学"的研究。 DS中衰老和神经退行性变之间相互作用的潜在机制”。该提案涉及 这些目标通过DS-AD链接在DS个体的睡眠障碍中。老年痴呆症与 (AD)和DS是有据可查的，但它们背后的机制却知之甚少。一个强大 候选物是淀粉样前体蛋白（APP）的裂解产物，Aβ，一种定义性组织病理学标志物 导致睡眠功能障碍另一个候选的21三体基因，钙调神经磷酸酶1的调节子 （RCAN 1），影响昼夜节律功能并促进AD相关病理。该提案重点关注APP和 RCAN 1过表达是DS和AD相关疾病之间的机制联系，涉及睡眠中断， 昼夜节律失调、认知障碍和突触缺陷。我们的初步数据表明， 遗传操作恢复Rcan 1到正常水平挽救了DS模型中的睡眠障碍。因此，我们认为， 我们的中心假设是，DS中RCAN 1的三倍增加促进了睡眠障碍并加重了AD， 相关病理学然而，由于APP和Aβ42扰乱睡眠并诱导认知缺陷，我们还将 评估APP过度表达在DS睡眠障碍中的作用。具体而言，我们将：1）确定影响 App和Rcan 1基因剂量校正对年龄依赖性睡眠中断和昼夜节律钟表达的影响 在DS模型小鼠中; 2）定量Rcan 1基因剂量校正对年龄依赖性突触缺陷的影响 和DS模型神经元中的网络激发特性;以及3）利用转录组分析的力量， 推测Dp 16小鼠睡眠中断的分子机制。建议的成果衡量标准 包括睡眠和昼夜行为评估;海马切片电生理学;多电极 DS衍生神经元培养物中的阵列（MEA）记录;无偏转录组分析;细胞因子蛋白 分析;以及神经胶质活化和病理性tau的免疫组织化学评价。我们的做法是 概念上和技术上的创新，因为APP和/或RCAN 1的作用还没有正式确定， 与DS-AD相关的睡眠异常。此外，MEA方法未用于研究DS中的睡眠 模型这项研究意义重大，因为尽管我们已经阐明了这些联系，APP或RCAN 1的作用 尚未研究过表达在促进DS相关睡眠或认知异常方面的作用。数据从 本项目的成功完成将开始填补一个关键的知识空白， APP/RCAN 1表达影响DS患者的睡眠障碍和AD样病理进展重要的是， 涉及APP/RCAN 1诱导的神经炎症过程的数据表明， 可以改善睡眠质量或减缓DS患者疾病进展的途径。