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。

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos 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&apos 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

项目摘要

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.

项目概要/摘要生物钟是我们内在的计时器，下丘脑视交叉上核 (SCN) 充当我们的计时器。中央起搏器协调整个身体的细胞自主振荡器。时钟发挥着基础作用在驱动节律组织和系统功能（例如认知和睡眠）中发挥作用。生理失调节律，包括睡眠/觉醒周期，越来越被认为是相关的关键病理生理因素患有阿尔茨海默病（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产生不利影响缺少核心时钟组件 BMAL1。然而，是否以及通过什么细胞和分子机制生物钟对 AD 病理学和疾病进展的影响仍知之甚少。我们先前生成了两个昼夜节律报告小鼠系，Per2::Luc 和 Per2::LucSV，对应于正常和增强的昼夜节律振荡。将这套强大的试剂与单细胞相结合生物发光成像，我们建议测试中心假设，即之间存在功能串扰大脑中的昼夜节律振荡和 AD 病理学，增强昼夜节律振荡可以减缓疾病通过基因表达和蛋白质聚集的调节来进展。我们提出两个具体目标。在目标 1 中，我们将确定脑时钟与 AD 进展之间的相互关系。我们将首先解决使用 Per2::Luc/APP-PS1 小鼠作为模型，质疑 AD 进展是否会导致 SCN 振荡器失调早发性家族性 AD 表达昼夜节律报告者。我们将进行单细胞生物发光成像确定单个振荡器中可能由 AD 引起的恶化和 SCN 中的耦合以及相位 SCN 和皮层/海马振荡器之间的关系。利用环境时差范例扰乱 SCN 的光输入路径，从而扰乱昼夜节律，我们将研究是否昼夜节律紊乱进而加剧疾病进展。在目标 2 中，我们将提出以下假设：振荡器的激活可以作为针对 AD 的干预策略。使用 Per2::LucSV/APP- PS1 小鼠，我们将确定增强的昼夜节律振荡是否会改善 AD 行为以及 Abeta 和 tau 病理学并维持昼夜节律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 AD 基因的影响。本项目的创新点包括昼夜节律振荡器作为 AD 的可修改因果因素的新颖概念框架，新的方法包括 Per2::LucSV 和单细胞生物发光成像，介入策略激活振荡器以延缓 AD 进展，并阐明新的分子和细胞机制连接昼夜节律振荡器和AD。这些研究可能最终会带来一种针对昼夜节律的新范式改善 AD 神经病理学和行为缺陷并减缓疾病进展的机制。