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 有620万美国人患有阿尔茨海默氏病（AD），生活质量降低和 认知功能不可逆地恶化。广告发展可能是由中央炎症驱动的 神经系统（CNS），但尚无广泛有效的疗法。我们建议AD病理可能是 在某种程度上是由周围免疫细胞通过中枢神经系统迁移的昼夜节律失调引起的。昼夜节律 时钟是生物过程的关键调节剂，在基因表达中产生约24小时的节奏， 释放和行为，但其在各种细胞和组织中的有效性随着年龄的增长而决定。多达70％的个人 伴有广告经验昼夜节律的破坏和睡眠效果，通常在临床前几年 诊断。因此 广告相关的病理。免疫系统受昼夜节律的严格调节，产生每日周期 免疫细胞在整个人体中迁移，导致高和低免疫反应性的暂时窗户。 免疫系统还严格调节中枢神经系统功能。外围感染会破坏行为并损害 认识。在衰老期间，中枢神经系统免疫系统逐渐从支持和反抗 针对更具反应性炎症状态的炎症功能。重要的是，贩运自适应免疫 细胞到免疫 - 脑接口调节神经炎症和认知。那我们假设那个昼夜节律 免疫细胞贩运中枢神经系统的节奏因年龄和类似广告状的病理而破坏，导致认知 和行为改变。该提议涉及以下特定目的：首先，确定昼夜节律的角色 CNS感染中免疫细胞运输的失调和衰老期间的认知下降 病理;其次，确定关键脑免疫接口细胞中分子钟的破坏是否加速 衰老和类似广告状病理学期间的认知能力下降；第三，揭示是否恢复日常贩运 通过时间限制的喂养节奏可以缓解年龄和广告诱导的病理。该建议是创新的 结合昼夜节律生物学，免疫学和行为神经科学方面的专业知识，以了解昼夜节律如何 通过中枢神经系统调节脑屏障和免疫细胞运输，调节衰老和类似AD的病理。 这项贡献将是重要的，因为我们的结果将确定昼夜节律适应性免疫的调节 细胞通过中枢神经系统的迁移会影响局部神经免疫功能。我们希望我们的结果将确定 生物节律在控制神经炎症病理学和通过免疫细胞认知控制中的新作用 迁移，突出了新型的热途径，以靶向认知能力下降和衰老的行为变化， 广告和与广告相关的痴呆症。