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 计划重点关注唐氏综合症患者的关键健康和生活质量需求 该使命的一部分是“针对疾病开展有针对性的、高风险的、高回报的基础科学研究。 此外，NIA 正在优先开展旨在“了解分子机制”的研究。 该提案阐述了 DS 中衰老和神经退行性疾病之间相互作用的潜在机制”。 DS-AD 的这些目标与 DS 个体的睡眠障碍之间存在联系。 (AD) 和 DS 都有详细记录，但人们对它们的基本机制知之甚少。 候选者是淀粉样前体蛋白 (APP)、Aβ 的裂解产物，Aβ 是一种定义的组织病理学标记物 AD 的另一个候选三体 21 基因，钙调神经磷酸酶 1 的调节因子。 (RCAN1)，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 RCAN1 过度表达是 DS 和 AD 相关疾病之间的机制联系，涉及睡眠中断， 我们的初步数据表明，昼夜节律失调、认知障碍和突触缺陷。 通过基因操作将 Rcan1 恢复到正常水平可以挽救 DS 模型中的睡眠障碍。 我们的中心假设是 DS 中的 RCAN1 三倍体会促进睡眠障碍并使 AD 恶化 然而，由于 APP 和 Aβ42 会扰乱睡眠并诱发认知缺陷，我们也会出现这种情况。 具体来说，我们将评估 APP 过度表达在 DS 睡眠障碍中的作用：1) 确定影响。 App 和 Rcan1 基因剂量校正对年龄依赖性睡眠中断和生物钟表达的影响 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放电特性；3) 利用转录组分析的力量 推断 Dp16 小鼠睡眠中断的分子机制。 包括睡眠和昼夜节律行为评估； DS 来源的神经元培养物中的阵列 (MEA) 记录；无偏转录组分析； 我们的方法是对神经胶质细胞活化和病理性 tau 蛋白进行免疫组织化学评估。 概念和技术上的创新，因为 APP 和/或 RCAN1 的作用尚未正式确定 此外，MEA 方法尚未用于研究 DS 中的睡眠。 这项研究很重要，因为尽管我们已经阐述了这些联系，但 APP 或 RCAN1 的作用仍然存在。 过度表达对促进 DS 相关睡眠或认知异常的影响尚未得到研究。 该项目的成功完成将通过确定如何开始填补关键的知识空白 APP/RCAN1 表达影响 DS 中的睡眠障碍和 AD 样病理进展。 涉及 APP/RCAN1 诱导的神经炎症过程的数据表明潜在的治疗方法 可以改善 DS 个体睡眠质量或减缓疾病进展的途径。