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; 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包括主动权侧重于关键的健康和生活质量需求 综合征（DS）。该任务的一部分是“开展针对性，高风险，高回报的基础科学研究 染色体21.“此外，NIA正在优先考虑旨在了解分子的研究 DS中衰老和神经变性之间相互作用的机制。 这些目标是DS个人睡眠障碍中的DS-AD链接。阿尔茨海默氏病之间的联系 （AD）和DS有充分的文献记录，但是它们的基础机制几乎没有理解。强壮 候选者是淀粉样蛋白前体蛋白（APP），Aβ的切割产物，Aβ，定义的组织病理学标记物 促进睡眠功能障碍的AD。另一个候选三体21基因，钙调蛋白的调节剂 （RCAN1），影响昼夜节律的功能并促进与广告相关的病理。该建议重点介绍应用程序和 RCAN1过表达作为与睡眠中断有关的DS与广告相关疾病之间的机械联系， 昼夜节律失调，认知障碍和突触缺陷。我们的初步数据表明 将RCAN1恢复到正常水平的遗传操作在DS模型中挽救了睡眠障碍。所以， 我们的核心假设是DS中的RCAN1三次三次促进了睡眠障碍，并加剧了AD- 相关病理。但是，由于APP和Aβ42破坏睡眠并诱发认知缺陷，我们也将 评估APP过表达在DS睡眠障碍中的作用。具体来说，我们将：1）确定效果 APP和RCAN1基因剂量校正在年龄依赖性睡眠中断和昼夜节律表达 在DS模型小鼠中； 2）量化RCAN1基因剂量校正对年龄依赖性突触缺陷的影响 DS模型神经元中的网络射击属性； 3）利用转录组分析的力量 推断DP16小鼠睡眠破坏的分子机制。提案的结果指标 包括睡眠和昼夜行为评估；海马切片电生理学；多电极 DS衍生的神经元文化中的阵列（MEA）记录；公正的转录组分析；细胞因子蛋白 测定；以及神经胶质激活和病理tau的免疫组织化学评估。我们的方法是 从概念和技术上创新，因为应用程序和/或RCAN1的作用尚未正式 在DS-AD连接的睡眠异常中考虑。此外，MEA方法不用于研究DS中的睡眠 模型。这项研究很重要，因为，Dospite我们已经阐明的链接，App或rcan1的作用 尚未研究促进与DS相关的睡眠或认知异常的过表达。来自 该项目的成功完成将开始填补关键知识差距，通过确定如何 APP/RCAN1表达会影响DS中AD样病理的睡眠障碍和AD类似病理的进展。重要的是， 暗示应用程序/RCAN1诱导的神经炎症过程的数据将表明潜在的治疗 DS个体中可以改善睡眠质量或疾病进展缓慢的途径。