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.

抽象的阿尔茨海默氏病是一种毁灭性的慢性神经退行性疾病，是痴呆症的主要原因老年人。阿尔茨海默氏病的标志性病理之一是细胞外的积累淀粉样蛋白β（Aβ）在大脑的受影响区域中“斑块”。在这笔赠款中，我们旨在了解如何两个不同但可能相互关联的物理过程，昼夜节律和血脑屏障（BBB）可以相互作用以调节阿尔茨海默氏病的病理生理。生物节奏是由昼夜节律策划并在大多数生物中运行，并允许我们的期待生理需求与白天和黑夜的替代周期产生共鸣。他们包括每日节奏睡眠效果周期，体温和外围器官的代谢活性。近年来，在两个人的研究中都发现了昼夜节律的扰动与阿尔茨海默氏病之间的联系和老鼠。值得注意的是，患有阿尔茨海默氏病的人对他们的24小时节奏表现出深刻的破坏睡眠效果和活动模式通常是在临床症状发作之前。还发现在这种疾病的早期，阿尔茨海默氏症患者的BBB功能障碍，生物标志物的功能障碍功能障碍可能可以预测这些人的未来认知能力下降。 BBB是一个曾经的术语描述血管使中枢神经系统（CNS）血管的独特特性。屏障由物理，运输，信号和代谢特性组成，允许内皮细胞（ECS）那条血管将血管紧密调节离子，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。在我们的初步研究中，我们已经确定对BBB外排的昼夜振荡，这种节奏是由大脑EC中昼夜节律调节剂BMAL1的内在表达。 BBB外排运输已经证明对从大脑清除Aβ至关重要。因此，我们提出了以下假设 BBB的节奏性导致Aβ清除率的功能障碍，加剧了阿尔茨海默氏症的病理生理学疾病。在此提案中，我们将解决几个重要问题，以了解生物节奏和 BBB可能相互作用，这两种生理学的功能障碍如何在进展中起作用阿尔茨海默氏病。首先，我们将使用一系列一系列结构，功能和基因表达分析在白天和黑夜的不同时间点上，以确定BBB的哪些特性显示昼夜振荡。其次，我们将确定BBB的节奏性是否受到内在EC的调节昼夜节律时钟，上核（SCN）中的中央昼夜节律，和/或由光或食物。第三，使用阿尔茨海默氏病小鼠模型，我们将确定BBB功能障碍是否功能障碍节奏调节阿尔茨海默氏病的病理生理学。该建议将阐明是否 EC节奏的功能障碍是阿尔茨海默氏病病理生理学的重要组成部分。