Neurovascular circadian oscillation in health and Alzheimer's disease

健康和阿尔茨海默病中的神经血管昼夜节律振荡

• 批准号: 10655154
• 负责人: Richard Daneman
• 金额: $ 196.61万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655154
• 关键词: ARNTL gene; Abeta clearance; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Automobile Driving; Biological Factors; Biological Markers; Biological Rhythm; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Body Temperature; Brain; Brain region; Cell Line; Cells; Central Nervous System; Chronic; Circadian Rhythms; Clinical; Data; Dementia; Development; Disease; Elderly; Endothelial Cells; Environment; Environmental Risk Factor; Exhibits; Extravasation; Food; Functional disorder; Future; Gene Expression Profiling; Genes; Grant; Health; Hemorrhage; Hour; Human; Immune; Impaired cognition; Individual; Ions; Knock-out; Light; Link; Magnetic Resonance Imaging; Mediating; Memory impairment; Metabolic; Metabolism; Movement; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Organ; Organism; Pathogenesis; Pattern; Peptides; Periodicity; Peripheral; Persons; Physiological; Physiological Processes; Physiology; Play; Property; Regulation; Role; Senile Plaques; Series; Serum; Signal Transduction; Sleep; Sleep Wake Cycle; Symptoms; Testing; Tight Junctions; Tissues; Tracer; Vascularization; abeta deposition; blood-brain barrier function; brain endothelial cell; circadian; circadian pacemaker; endothelial dysfunction; extracellular; feeding; glymphatic system; immunoregulation; light entrainment; mouse model; neural; neurovascular; novel; receptor; solute; suprachiasmatic nucleus; transcytosis

ABSTRACT Alzheimer’s disease is a devastating chronic neurodegenerative disease and the leading cause of dementia in older adults. One of the hallmark pathologies of Alzheimer’s disease is the accumulation of extracellular amyloid-beta (Aβ) “plaques” throughout affected regions of the brain. In this grant we aim to understand how two different but potentially inter-related physiological processes, circadian rhythms and the blood-brain barrier (BBB), may interact to regulate the pathophysiology of Alzheimer’s disease. Biological rhythms are orchestrated by the circadian clock and operate in most organisms, and allow for the anticipation of our physiological needs to resonate with the alternating cycles of day and night. They include the daily rhythmicity of the sleep-wake cycle, body temperature, and the metabolic activity of peripheral organs. In recent years, a link between perturbation of circadian rhythms and Alzheimer’s disease was found in studies of both humans and mice. Notably, people with Alzheimer’s disease exhibit profound disruptions to their 24 hour rhythms in sleep-wake and activity patterns, often preceding the onset of clinical symptoms. It has also been found that there is dysfunction of the BBB in Alzheimer’s patients early in the disease, and that biomarkers of this dysfunction may be predictive of future cognitive decline in these individuals. The BBB is a term used to describe the unique properties of the blood vessels that vascularize the central nervous system (CNS). This barrier consists of physical, transport, signaling and metabolic properties that allow the endothelial cells (ECs) that line the blood vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain, thus controlling the extracellular environment of the neural tissue. In our preliminary studies, we have identified that there is a diurnal oscillation to BBB efflux transport, and that this rhythmicity is regulated by the intrinsic expression of the circadian clock regulator BMAL1 within brain ECs. BBB efflux transport has been shown to be critical in the clearance of Aβ from the brain. Therefore, we propose the hypothesis that loss of BBB rhythmicity leads to dysfunction of Aβ clearance, exacerbating the pathophysiology of Alzheimer’s disease. In this proposal we will address several important questions to understand how biological rhythms and the BBB may interact, and how dysfunction of these two physiologies may play a role in the progression of Alzheimer’s disease. First, we will use a series of series of structural, functional, and gene expression analyses across different timepoints of day and night to determine which properties of the BBB display diurnal oscillation. Second, we will determine whether the rhythmicity of the BBB is regulated by the intrinsic EC circadian clock, the central circadian clock in the suprachiasmatic nucleus (SCN), and/or is entrained by light or food. Third, using a mouse model of Alzheimer’s disease, we will determine whether dysfunction of BBB rhythmicity regulates the pathophysiology of Alzheimer’s disease. This proposal will shed light as to whether dysfunction of the EC rhythmicity is an important component of Alzheimer’s disease pathophysiology.

摘要 阿尔茨海默氏病是一种破坏性的慢性神经退行性疾病，是老年痴呆症的主要原因。 老年人阿尔茨海默病的标志性病理之一是细胞外基质的积累， 淀粉样蛋白-β（Aβ）“斑块”遍布大脑的受影响区域。在这项资助中，我们的目标是了解如何 两种不同但可能相互关联的生理过程，昼夜节律和血脑屏障 (BBB)可能相互作用以调节阿尔茨海默病的病理生理学。生物节律是 由生物钟协调，在大多数生物体中运作，并允许我们的预期， 生理需要与昼夜交替的周期产生共鸣。包括每天的节奏 睡眠-觉醒周期、体温和外周器官的代谢活动。近年来 在对两个人的研究中发现了昼夜节律紊乱和阿尔茨海默病之间的联系 和老鼠。值得注意的是，阿尔茨海默病患者的24小时节律受到严重破坏， 睡眠-觉醒和活动模式，通常在临床症状发作之前。还发现 阿尔茨海默病患者在疾病早期存在血脑屏障功能障碍， 功能障碍可能预示着这些个体未来的认知能力下降。BBB是一个术语， 描述了使中枢神经系统（CNS）血管化的血管的独特性质。这 屏障由物理、运输、信号传导和代谢特性组成，其允许内皮细胞（EC） 它们排列在血管中，严格调节血液中离子、分子和细胞的运动。 和大脑，从而控制神经组织的细胞外环境。在初步研究中，我们 已经确定BBB流出物运输存在昼夜振荡，并且这种节律性由以下因素调节： 脑内皮细胞内生物钟调节因子BMAL 1的内在表达。血脑屏障外排转运已被 在Aβ从大脑中清除的过程中起着关键作用。因此，我们提出假设， BBB节律性导致Aβ清除功能障碍，加重阿尔茨海默病的病理生理学 疾病在这个建议中，我们将解决几个重要的问题，以了解生物节律和 血脑屏障可能相互作用，以及这两种生理功能障碍如何在脑血管病的进展中发挥作用。 老年痴呆症首先，我们将使用一系列的结构，功能和基因表达分析 在白天和夜晚的不同时间点，以确定BBB的哪些特性显示昼夜性 振荡第二，我们将确定血脑屏障的节律性是否受内源性EC的调节 昼夜节律钟，视交叉上核（SCN）中的中央昼夜节律钟，和/或被光携带，或 食物第三，使用阿尔茨海默病小鼠模型，我们将确定是否BBB功能障碍， 节律性调节阿尔茨海默病的病理生理学。这一建议将阐明， EC节律性的功能障碍是阿尔茨海默病病理生理学的重要组成部分。