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

项目摘要/摘要 生物钟是我们内在的计时器，其中下丘脑视交叉上核(SCN)起着 中央起搏器，协调全身细胞自主振荡器。时钟发挥着基础性作用 在驱动节律组织和系统功能方面的作用，如认知和睡眠。生理失调 节律，包括睡眠/清醒周期，越来越被认为是一个关键的病理生理因素。 患有阿尔茨海默病(AD)。生物钟的紊乱已被证明会导致基因异常 表达和神经变性，以及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BMAL1。然而，是否以及通过什么细胞和分子机制 生物钟在AD的病理中起作用，疾病的进展仍然知之甚少。我们 之前生成的两个昼夜节律报告鼠系PER2：：Luc和PER2：：LucSV，对应于正常 和增强的昼夜节律振荡。将这套强大的试剂集与单细胞 生物发光成像，我们建议检验中心假设之间存在功能串扰 大脑中的昼夜节律振荡器和AD病理，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而进展。我们提出了两个具体目标。在目标1中， 我们将确定大脑时钟和AD进展之间的相互关系。我们将首先解决 以PER2：：Luc/APP-PS1小鼠为模型探讨AD进展是否影响SCN振荡器 表现为昼夜节律的早发性家族性AD。我们将进行单细胞生物发光成像 确定可能由AD引起的单个振荡器的恶化和SCN中的耦合，以及相位 SCN与皮层/海马区振荡器的关系使用环境时差范式来 打乱到SCN的光输入通路，从而破坏昼夜节律，我们将调查 昼夜节律的紊乱反过来又加剧了疾病的发展。在目标2中，我们将解决以下假设 振荡器的激活可以作为对抗AD的一种干预策略。使用PER2：：LucSV/APP- PS1小鼠，我们将确定增强的昼夜节律振荡是否改善AD行为以及Abeta和tau 在昼夜节律行为和睡眠结构中保持稳健性。我们将进一步确定 昼夜节律增强对可能的钟控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原因因素，以对抗AD，新的 包括PER2：：LucSV和单细胞生物发光成像在内的方法学，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 把昼夜节律振荡器和AD联系起来。这些研究可能最终导致一种针对昼夜节律的新范式 改善阿尔茨海默病和钝性疾病进展的神经病理和行为缺陷的机制。

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.