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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

抽象的阿尔茨海默病是一种毁灭性的慢性神经退行性疾病，也是导致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物质的积累。 β 淀粉样蛋白（Aβ）在整个大脑受影响区域中形成“斑块”，在这项资助中，我们旨在了解如何形成斑块。昼夜节律和血脑屏障是两种不同但可能相互关联的生理过程 (BBB)，可能相互作用来调节阿尔茨海默病的病理生理学生物节律。由生物钟精心编排并在大多数生物体中运作，并允许我们预期生理需要与昼夜交替周期产生共鸣，其中包括日常节律。近年来，研究人员对睡眠-觉醒周期、体温和外周器官的代谢活动进行了研究。对人类的研究发现昼夜节律紊乱与阿尔茨海默病之间存在联系值得注意的是，患有阿尔茨海默病的人的 24 小时节律受到严重破坏。睡眠-觉醒和活动模式，通常在临床症状出现之前。阿尔茨海默病患者在疾病早期就存在血脑屏障功能障碍，并且这种功能的生物标志物功能障碍可能预示着这些人未来的认知能力下降。描述使中枢神经系统 (CNS) 血管化的血管的独特特性。屏障由物理、运输、信号传导和代谢特性组成，允许内皮细胞 (EC) 排列在血管中，严格调节血液之间离子、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。已经确定 BBB 外排运输存在昼夜振荡，并且这种节律性受以下因素调节：生物钟调节器 BMAL1 在脑内皮细胞 (BBB) 流出转运中的内在表达已被证实。研究表明，Aβ 对大脑中的清除至关重要，因此，我们提出以下假设：Aβ 的缺失。 BBB 节律性导致 Aβ 清除功能障碍，加剧阿尔茨海默病的病理生理学在本提案中，我们将解决几个重要问题，以了解生物节律和疾病的关系。 BBB 可能相互作用，以及这两种生理机能的功能障碍如何在 BBB 的进展中发挥作用首先，我们将使用一系列结构、功能和基因表达分析。跨越白天和夜晚的不同时间点，以确定 BBB 显示昼夜的哪些属性其次，我们将确定 BBB 的节律是否受到内在 EC 的调节。生物钟，视交叉上核（SCN）中的中央生物钟，和/或由光或第三，利用阿尔茨海默病小鼠模型，我们将确定血脑屏障是否功能障碍。节律性调节阿尔茨海默氏病的病理生理学。 EC节律性功能障碍是阿尔茨海默病病理生理学的重要组成部分。