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: 10688103
• 负责人: Laura K Fonken
• 金额: $ 58.4万
• 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/10688103
• 关键词: 3xTg-AD mouse; ARNTL gene; Address; Affect; Age; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; American; Anti-Inflammatory Agents; Area; Arrhythmia; Behavior; Behavioral; Behavioral Symptoms; Biological Process; Biological Rhythm; Brain; Cell Adhesion; Cells; Central Nervous System; Choroid Plexus Epithelium; Circadian Dysregulation; Circadian Rhythms; Cognition; Cognitive; Darkness; Dementia; Dependence; Deterioration; Development; 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; Neurobehavioral Manifestations; Neuroimmune; Neurosciences; Newly Diagnosed; Organ; Pathologic; Pathology; Patients; Periodicity; Peripheral; Persons; 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-restricted feeding; Tissues; aged; aging brain; 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; immunoregulation; improved; in vivo; inflammatory modulation; innovation; insight; lymphatic vasculature; migration; molecular clock; neuroinflammation; neuropathology; new therapeutic target; novel; novel strategies; novel therapeutics; pharmacologic; 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.

项目概要 620 万美国人患有阿尔茨海默病 (AD)，生活质量下降，并且 AD 发展的不可逆转的恶化可能是由中枢炎症引起的。 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中枢神经系统迁移的昼夜节律失调所致。 生物钟是生物过程的关键调节因子，在基因表达、激素等方面产生约 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的增长而下降，高达 70% 的个体。 患有 AD 的人会经历昼夜节律紊乱和睡眠-觉醒障碍，这些症状通常在临床出现前数年就出现 因此，昼夜节律失调是年龄和早期干预的潜在生物标志物和信号。 AD 相关病理学 免疫系统受到生物钟的严格调节，产生每日周期。 免疫细胞在全身迁移，导致高和低免疫反应性的时间窗口。 免疫系统还严重调节中枢神经系统功能；周围炎症会扰乱行为并损害健康。 在衰老过程中，中枢神经系统免疫系统逐渐从亲和抗之间的平衡转变。 炎症功能转向更具反应性的炎症状态，重要的是，适应性免疫的运输。 细胞与免疫-大脑接口调节神经炎症和认知，因此，我们在昼夜节律中挣扎。 免疫细胞向中枢神经系统运输的节律会随着年龄和 AD 样病理而被打乱，从而导致认知障碍 该提案涉及以下具体目标：首先，确立昼夜节律的作用。 中枢神经系统炎症中的免疫细胞运输失调以及衰老和 AD 样认知能力下降 病理学；其次，确定关键脑免疫界面细胞中分子钟的破坏是否会加速 衰老期间的认知能力下降和类似 AD 的病理学；第三，揭示是否恢复日常贩运 通过限时喂养控制节律可以改善年龄和 AD 引起的病理。 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 通过中枢神经系统调节脑屏障和免疫细胞运输可调节衰老和 AD 样病理。 这一贡献将是意义重大的，因为我们的结果将确定适应性免疫的昼夜节律调节如何 通过中枢神经系统的细胞迁移会影响局部神经免疫功能。 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，强调针对衰老过程中认知衰退和行为变化的新治疗途径， AD 和 AD 相关痴呆症。

项目成果

Effects of dim light at night in C57BL/6J mice on recovery after spinal cord injury.

夜间弱光对 C57BL/6J 小鼠脊髓损伤后恢复的影响。

• 发表时间: 2024-01-09
• 作者: Aldrich, John C;Scheinfeld, Ashley R;Lee, Sydney E;Dusenbery, Kalina J;Mahach, Kathryn M;Van de Veire, Brigid C;Fonken, Laura K;Gaudet, Andrew D
• 通讯作者: Gaudet, Andrew D

Effects of dim light at night in C57BL/6 J mice on recovery after spinal cord injury.

夜间弱光对 C57BL/6J 小鼠脊髓损伤后恢复的影响。

• 发表时间: 2024-05
• 影响因子: 5.3
• 作者: Aldrich, John C;Scheinfeld, Ashley R;Lee, Sydney E;Dusenbery, Kalina J;Mahach, Kathryn M;Van de Veire, Brigid C;Fonken, Laura K;Gaudet, Andrew D
• 通讯作者: Gaudet, Andrew D