Disrupted Circadian Regulation of Cell Migration at CNS-Immune Interfaces in Aging and Alzheimer's Disease

项目摘要 620万美国人患有阿尔茨海默病(AD)，生活质量下降， 认知功能不可逆转的恶化。AD的发展可能是由中央的炎症驱动的 神经系统(CNS)，但仍没有广泛有效的治疗方法。我们认为AD的病理可能是， 部分原因是外周免疫细胞通过中枢神经系统迁移的昼夜节律失调所致。昼夜节律 时钟是生物过程的关键调节器，在基因表达、激素等方面产生~24小时的节奏 释放和行为，但其在各种细胞和组织中的效力随着年龄的增长而恶化。高达70%的个人 有AD经历的昼夜节律紊乱和睡眠-觉醒障碍，通常出现在临床前数年 诊断。因此，昼夜节律失调是一种潜在的生物标志物和信号，可用于早期干预年龄和 与AD相关的病理学。免疫系统受到生物钟的严格控制，每天产生 免疫细胞在体内的迁移导致免疫反应性的高和低的时间窗口。 免疫系统也对中枢神经系统的功能起着重要的调节作用；外周炎症会扰乱行为并损害 认知力。在衰老过程中，中枢神经系统的免疫系统逐渐从支持和反对之间的平衡转变 炎症功能向更具反应性的炎症状态转变。重要的是，适应性免疫的贩运 细胞到免疫-大脑的接口调节神经炎症和认知。因此，我们假设昼夜节律 免疫细胞转运到中枢神经系统的节律被年龄和AD样病理打乱，导致认知 以及行为上的改变。这项建议涉及以下具体目标：第一，确立生物钟的作用 衰老和类AD时中枢神经系统炎症和认知功能减退中免疫细胞转运的失调 第二，确定关键的大脑免疫接口细胞的分子时钟的破坏是否会加速 衰老过程中的认知衰退和AD样病理；第三，揭示是否恢复日常贩卖 通过限时喂养的节律可以改善年龄和AD诱导的病理。这项建议在以下方面具有创新性 结合昼夜节律生物学、免疫学和行为神经科学的专业知识来了解昼夜节律是如何 通过中枢神经系统调节脑屏障和免疫细胞的运输，调节衰老和类似AD的病理。 这一贡献将是重要的，因为我们的结果将确定获得性免疫的昼夜调节 细胞通过中枢神经系统的迁移影响局部神经免疫功能。我们预计我们的结果将确定一个 生物节律通过免疫细胞调节神经炎性病理和认知的新作用 迁移，强调了针对认知衰退和衰老中的行为变化的新的治疗途径， AD和AD相关痴呆。

Project Summary 6.2 million Americans are living with Alzheimer’s disease (AD), experiencing reduced quality of life and irreversible deterioration of cognitive function. AD development is likely driven by inflammation in the central nervous system (CNS), yet there remain no broadly effective therapies. We propose that AD pathology may be, in part, caused by circadian dysregulation of peripheral immune cell migration through the CNS. The circadian clock is a critical regulator of biological processes, generating ~24 h rhythms in gene expression, hormone release, and behavior, but its efficacy in various cells and tissues deteriorates with age. Up to 70% of individuals with AD experience circadian disruption and sleep-wake disturbances, which often present years before clinical diagnosis. Circadian dysregulation is therefore a potential biomarker and signal for early intervention in age- and AD-related pathology. The immune system is tightly regulated by the circadian clock, generating daily cycles of immune cell migration throughout the body which leads to temporal windows of high and low immune reactivity. The immune system also critically regulates CNS function; peripheral inflammation disrupts behavior and impairs cognition. During aging, the CNS immune system gradually shifts from a balance between pro- and anti- inflammatory function towards a more reactive inflammatory state. Importantly, trafficking of adaptive immune cells to immune-brain interfaces regulates neuroinflammation and cognition. Thus, we hypothesize that circadian rhythms in immune cell trafficking to the CNS are disrupted with age and AD-like pathology, leading to cognitive and behavioral changes. This proposal addresses the following specific aims: First, establish the role of circadian dysregulation of immune cell trafficking in CNS inflammation and cognitive decline during aging and AD-like pathology; second, determine if disruption of molecular clocks in key brain-immune interface cells expedites cognitive decline during aging and AD-like pathology; and third, reveal whether reinstating daily trafficking rhythms via time-restricted feeding ameliorates age- and AD-induced pathology. This proposal is innovative in combining expertise in circadian biology, immunology, and behavioral neuroscience to understand how circadian regulation of brain barriers and immune cell trafficking through the CNS regulates aging and AD-like pathology. This contribution will be significant because our results will identify how circadian regulation of adaptive immune cell migration through the CNS affects local neuroimmune function. We expect that our results will identify a novel role for biological rhythms in regulating neuroinflammatory pathology and cognition via immune cell migration, highlighting novel therapeutic avenues to target cognitive decline and behavioral changes in aging, AD, and AD-related dementia.