Functional crosstalk between brain circadian oscillators and AD pathology in mouse models.

小鼠模型中大脑昼夜节律振荡器与 AD 病理学之间的功能串扰。

• 批准号: 9902300
• 负责人: Seung-Hee Yoo
• 金额: $ 15.48万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902300
• 关键词: APP-PS1; ARNTL gene; Ablation; Address; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Automobile Driving; Behavior; Behavioral; Biological; Biological Assay; Biological Markers; Biological Rhythm; Biology; Bioluminescence; Brain; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Cognition; Collaborations; Coupling; DNA Sequence Alteration; Deterioration; Disease; Disease Progression; Early Onset Familial Alzheimer' s Disease; Environment; Exhibits; Functional disorder; Gene Abnormality; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic Enhancement; Hippocampus (Brain); Hypothalamic structure; Impaired cognition; Individual; Intervention; Jet Lag Syndrome; Knock-in; Lead; Light; Link; Luciferases; Measures; Memory impairment; Methodology; Microscopy; Modeling; Modernization; Molecular; Monitor; Morale; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Pacemakers; Pathologic; Pathology; Pathway interactions; Periodicity; Peripheral; Pharmacology Study; Phase; Physiological; Physiology; Pilot Projects; Play; Proteins; Public Health; Reagent; Reporter; Research; Risk Factors; Role; Senile Plaques; Sleep; Sleep Architecture; Sleep Wake Cycle; Sleep disturbances; Societies; Syndrome; Testing; Therapeutic; Tissues; Transgenic Mice; abeta accumulation; bioluminescence imaging; brain tissue; cellular imaging; circadian; circadian pacemaker; circadian regulation; combat; improved; innovation; modifiable risk; mouse model; novel; overexpression; protein aggregation; spatiotemporal; suprachiasmatic nucleus; tau Proteins; translational impact

PROJECT SUMMARY / ABSTRACT The circadian clock is our intrinsic timer where the hypothalamic suprachiasmatic nuclei (SCN) serves as a central pacemaker to orchestrate cell-autonomous oscillators throughout the body. The clock plays fundamental roles in driving rhythmic tissue and systemic functions such as cognition and sleep. Dysregulated physiological rhythms, including sleep/wake cycles, are increasingly appreciated as a key pathophysiological factor associated with Alzheimer's disease (AD). Disruption of the circadian clock has been shown to cause abnormal gene expression and neurodegeneration, and recent studies indicated adverse impact on amyloid dynamics in mice lacking the core clock component BMAL1. However, whether and by what cellular and molecular mechanisms the circadian clock contributes to AD pathology and disease progression remains poorly understood. We previously generated two circadian reporter mouse lines, Per2::Luc and Per2::LucSV, corresponding to normal and enhanced circadian oscillation respectively. Combining this powerful reagent set with single-cell bioluminescence imaging, we propose to test the central hypothesis that there is a functional crosstalk between circadian oscillators in the brain and AD pathology, and enhancing circadian oscillation can decelerate disease progression via regulation of gene expression and protein aggregation. We propose two specific aims. In Aim 1, we will determine a reciprocal relationship between brain clocks and AD progression. We will first address the question whether AD progression dysregulates SCN oscillators using Per2::Luc/APP-PS1 mice as a model of early-onset familial AD expressing a circadian reporter. We will perform single-cell bioluminescence imaging to determine a possible AD-induced deterioration in individual oscillators and coupling in the SCN, as well as phase relationship between SCN and cortex/hippocampus oscillators. Using an environmental jet-lag paradigm to disrupt the light input pathway to the SCN and consequently circadian rhythms, we will investigate whether circadian disruption in turn exacerbates disease progression. In Aim 2, we will address the hypothesis that activation of the oscillator can be deployed as an interventional strategy against AD. Using Per2::LucSV/APP- PS1 mice, we will determine whether enhanced circadian oscillation ameliorates AD behavior and Abeta and tau pathology and sustains robustness in circadian behavioral and sleep architecture. We will further determine the effects of circadian enhancement on putative clock-controlled AD genes. The innovations of this project include a novel conceptual framework of the circadian oscillator as a modifiable causal factor against AD, the new methodologies including Per2::LucSV and single-cell bioluminescence imaging, the interventional strategy of activating the oscillator to delay AD progression, and the elucidation of new molecular and cellular mechanisms linking the circadian oscillator and AD. The studies may ultimately lead to a new paradigm of targeting circadian machinery to improve neuropathological and behavioral deficits in AD and blunt disease progression.

项目总结/摘要 昼夜节律钟是我们的内在计时器，下丘脑视交叉上核（SCN）作为一种生物钟， 中枢起搏器协调全身细胞自主振荡器。时钟播放基本 在驱动节律组织和系统功能（如认知和睡眠）中的作用。生理失调 节律，包括睡眠/觉醒周期，越来越多地被认为是一个关键的病理生理因素， 阿尔茨海默病（AD）生物钟的破坏已被证明会导致基因异常， 表达和神经变性，最近的研究表明对小鼠淀粉样蛋白动力学的不利影响 缺少核心时钟组件BMAL 1。然而，是否以及通过什么细胞和分子机制， 昼夜节律钟对AD病理学和疾病进展的贡献仍然知之甚少。我们 先前产生了两个昼夜节律报告小鼠系，Per 2：：Luc和Per 2：：LucSV，对应于正常 和增强的昼夜节律振荡。将这种强大的试剂组合与单细胞 生物发光成像，我们建议测试中心假设，有一个功能串扰之间 昼夜节律振荡器在大脑和AD病理，并加强昼夜节律振荡可以减缓疾病 通过调节基因表达和蛋白质聚集而进展。我们提出两个具体目标。在目标1中， 我们将确定脑时钟和AD进展之间的相互关系。我们将首先讨论 使用Per 2：：Luc/APP-PS1小鼠作为AD模型， 表达昼夜节律报告基因的早发性家族性AD。我们将进行单细胞生物发光成像， 确定单个振荡器和SCN中的耦合以及相位中可能的AD引起的劣化 SCN与皮层/海马振荡器之间的关系。使用环境时差范例， 扰乱SCN的光输入途径，从而破坏昼夜节律，我们将研究是否 昼夜节律的破坏反过来加剧了疾病的进展。在目标2中，我们将讨论以下假设： 振荡器的激活可以作为对抗AD的介入策略来部署。使用Per 2：：LucSV/APP- PS1小鼠，我们将确定增强的昼夜节律振荡是否改善AD行为和Abeta和tau蛋白 病理和维持昼夜行为和睡眠结构的稳健性。我们将进一步确定 昼夜节律增强对假定的时钟控制的AD基因的影响。该项目的创新之处包括 一个新的概念框架的昼夜节律振荡器作为一个可修改的因果因素对AD，新的 方法包括Per 2：：LucSV和单细胞生物发光成像， 激活振荡器以延迟AD进展，并阐明新的分子和细胞机制 联系昼夜节律振荡器和AD这些研究最终可能会导致一种新的模式， 改善AD中的神经病理学和行为缺陷并减缓疾病进展的机制。