Project 3: Circadian rhythms in regulation of ABeta pathology and brain oxidative stress

项目3项目概要/摘要 活动、睡眠-觉醒周期和其他生理参数中的昼夜节律的破坏是一种 这是衰老的结果，并且在阿尔茨海默病（AD）中显著发生。虽然昼夜节律紊乱是一种 AD发病的主要原因，但尚不清楚它是否有助于疾病的发病机制。系统性昼夜节律 小鼠和人类的节律由下丘脑的视交叉上核（SCN）调节， 核心时钟基因在所有器官中随光暗周期的外周振荡。我们的初步 数据显示，调节昼夜节律转录的核心昼夜节律钟基因的遗传缺失， 振荡，可导致神经元氧化应激和神经变性，这表明，破坏整个- 动物SCN驱动的昼夜节律可能通过时钟基因失调对AD产生有害影响。 人类病理学研究表明，SCN是AD中的神经病理学部位，尽管SCN的影响可能与AD的发病机制有关。 功能障碍对AD发病机制的影响尚不清楚。本项目的目的是检验以下假设： 受损的SCN介导的昼夜节律将增加淀粉样蛋白β（A？）病理，突触损伤， AD小鼠模型和人类AD患者中的氧化应激。我们将研究如何损伤的 SCN，废除小鼠的系统性昼夜节律，改变睡眠-觉醒参数和昼夜节律， 在2种小鼠A？蓄积模型中的皮质和海马基因表达模式。我们将 确定SCN损伤是否加速了这些小鼠模型中的A？斑块沉积，并检查 SCN介导的节律影响A？诱导的突触损伤、神经炎症和氧化损伤。最后， 我们将研究活动的昼夜节律模式（活动记录）和脑脊液标志物之间的相关性， 老年人和临床前AD患者的氧化应激和AD病理学。这些研究 旨在揭示SCN介导的昼夜节律功能障碍是AD的一个促成因素 发病机制，这表明针对昼夜节律系统的治疗可能会预防或延迟AD。 ¿

Project 3 Project Summary/Abstract Disruption of circadian rhythms in activity, sleep-wake cycle, and other physiologic parameters is a consequence of aging, and occurs prominently in Alzheimer's Disease (AD). While circadian dysfunction is a major cause of morbidity in AD, it is unknown if it contributes to disease pathogenesis. Systemic circadian rhythms in mice and humans are regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, which synchronizes peripheral oscillations of core clock genes in all organs with the light-dark cycle. Our preliminary data shows that genetic deletion of core circadian clock genes, which mediate circadian transcriptional oscillations, can cause neuronal oxidative stress and neurodegeneration, suggesting that disruption of whole- animal SCN-driven circadian rhythms might have deleterious effects in AD through clock gene dysregulation. Human pathologic studies suggest that the SCN is a site of neuropathology in AD, though the impact of SCN dysfunction on AD pathogenesis is unknown. The objective of this Project is to test the hypothesis that impaired SCN-mediated circadian rhythms will increase amyloid-beta (A¿) pathology, synaptic injury, and oxidative stress in mouse models of AD and in human AD patients. We will examine how lesioning of the SCN, which abrogates systemic circadian rhythms in mice, alters sleep-wake parameters and circadian patterns of cortical and hippocampal gene expression in 2 mouse models of A¿ accumulation. We will determine if SCN lesioning accelerates A¿ plaque deposition in these mouse models, and examine if loss of SCN-mediated rhythms affects A¿-induced synaptic injury, neuroinflammation, and oxidative damage. Finally, we will examine correlations between circadian patterns in activity (actigraphy) and cerebrospinal fluid markers of oxidative stress and AD pathology in older adults and individuals with preclinical AD. These studies are designed to reveal dysfunction of SCN-mediated circadian rhythms as a contributing factor in AD pathogenesis, suggesting that therapies targeting the circadian system might prevent or delay AD. ¿