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

衰老和阿尔茨海默病中中枢神经系统免疫界面细胞迁移的昼夜节律调节被破坏

• 批准号: 10515951
• 负责人: Laura K Fonken
• 金额: $ 57.93万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515951
• 关键词: 3xTg-AD mouse; ARNTL gene; Address; Affect; Age; Aging; Alpha Rhythm; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; American; Anti-Inflammatory Agents; Area; Behavior; Behavioral; Behavioral Symptoms; Biological Process; Biological Rhythm; Brain; Cell Adhesion; Cells; Choroid Plexus Epithelium; Circadian Dysregulation; Circadian Rhythms; Cognition; Cognitive; Dementia; Dependence; Deterioration; Development; Diagnosis; Disease; Disease Progression; Early Intervention; Equilibrium; Gene Expression; Genetic; Goals; Homeostasis; Hormones; Immune; Immune system; Immunity; Immunology; Immunotherapy; Impaired cognition; Individual; Inflammation; Inflammatory; Investigation; Knock-out; Leukocyte Trafficking; Leukocytes; Light; Mediating; Meningeal; Meninges; Microglia; Mus; Nervous System Physiology; Neuraxis; Neurobehavioral Manifestations; Neuroimmune; Neurosciences; Organ; Pathologic; Pathology; Patients; Periodicity; Peripheral; Persons; Pharmacology; Phase; Phenotype; Physiological Processes; Population; Prevalence; Process; Protocols documentation; Quality of life; Research; Role; Signal Transduction; Sleep; Sleep Wake Cycle; Sleep disturbances; Structure of choroid plexus; System; T-Lymphocyte; Testing; Therapeutic; Time; Time-restricted feeding; Tissues; aged; aging brain; base; cell motility; circadian; circadian biology; circadian pacemaker; circadian regulation; clinical diagnosis; cognitive change; cognitive function; disability; effective therapy; experience; experimental study; human old age (65+); immune activation; immune function; improved; in vivo; inflammatory modulation; innovation; insight; lymphatic vasculature; migration; molecular clock; neuroinflammation; neuropathology; new therapeutic target; novel; novel strategies; novel therapeutics; potential biomarker; receptor; success; trafficking

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.

项目摘要 6.2数百万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的发展可能是由中枢神经系统的炎症驱动的。 神经系统（CNS），但仍然没有广泛有效的治疗方法。我们认为AD病理学可能是， 部分原因是外周免疫细胞通过CNS迁移的昼夜节律失调。昼夜 生物钟是生物过程的关键调节器，在基因表达、激素分泌和代谢中产生约24小时的节律。 释放和行为，但其在各种细胞和组织中的功效随着年龄而恶化。高达70%的人 AD患者经历昼夜节律紊乱和睡眠-觉醒障碍，通常在临床前数年出现 诊断.因此，昼夜节律失调是一种潜在的生物标志物和早期干预年龄和 AD相关病理学。免疫系统受到生物钟的严格调节，产生每日的免疫循环。 免疫细胞在整个身体中的迁移，这导致高和低免疫反应性的时间窗口。 免疫系统也严格调节中枢神经系统功能;外周炎症破坏行为和损害 认知.在衰老过程中，中枢神经系统免疫系统逐渐从亲和抗- 炎症功能向反应性更强的炎症状态转变。重要的是，适应性免疫的运输 细胞与免疫-脑界面调节神经炎症和认知。因此，我们假设昼夜节律 免疫细胞运输到CNS的节律随着年龄和AD样病理而被破坏，导致认知功能障碍。 和行为改变。该提案提出了以下具体目标：首先，建立昼夜节律的作用， 中枢神经系统炎症中免疫细胞运输的失调和衰老期间的认知下降以及AD样 病理学;第二，确定关键脑免疫界面细胞中分子钟的破坏是否加速了 衰老期间的认知能力下降和AD样病理;第三，揭示恢复日常贩运是否 通过时间限制喂养的节律改善了年龄和AD诱导的病理学。这一建议具有创新性， 结合昼夜节律生物学，免疫学和行为神经科学的专业知识，了解昼夜节律如何 脑屏障的调节和免疫细胞通过CNS的运输调节衰老和AD样病理。 这一贡献将是重要的，因为我们的研究结果将确定适应性免疫的昼夜节律调节 通过CNS的细胞迁移影响局部神经免疫功能。我们希望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症病理和认知的新作用 迁移，突出了针对衰老中认知能力下降和行为变化的新的治疗途径， AD和AD相关痴呆。