Changes in Cerebrovascular Function with Aging in Normal and AD Brain

正常脑和 AD 脑中脑血管功能随衰老的变化

基本信息

批准号：
10543141
负责人：
HARALD W SONTHEIMER
金额：
$ 48.09万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543141
关键词：
Ablation Acceleration Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amyloid Amyloid deposition Amyloidosis Animals Arteries Astrocytes Biological Blood Blood - brain barrier anatomy Blood Vessels Blood capillaries Blood flow Cell Separation Cerebral Amyloid Angiopathy Cerebrovascular Circulation Cerebrovascular system Cerebrum Chronic Control Animal Data Deposition Dinoprostone Disease Endothelium Functional disorder Gene Expression Genes Genetic Genomics Gliosis Health Hippocampus Hyperemia Impairment Lasers Longevity Magnetism Maintenance Matrix Metalloproteinases Modeling Mus Pathogenesis Pathologic Peptide Hydrolases Pericytes Positioning Attribute Process Protein Overexpression Proteins Proteome Proteomics Research Role Secondary to Senile Plaques Sex Differences Signal Induction Signal Transduction Smooth Muscle Specific qualifier value Structure Surface Tight Junctions Time Toxic effect Tracer Transgenic Mice Trees Vibrissae age related amyloid pathology arteriole cell type cerebrovascular clinically relevant experimental study familial Alzheimer disease functional decline functional disability gender difference healthy aging improved in vivo innovation mouse model multiphoton imaging neurotoxic neurovascular coupling neurovascular unit normal aging novel pathological aging protein expression sex transcriptome transcriptome sequencing

项目摘要

The surface of cerebral blood vessels is covered nearly entirely by astrocyte processes called endfeet. Astrocytic endfeet are perfectly positioned to interact with the endothelial vessel walls, and, where present, the surrounding smooth muscles or pericytes. Through the release of vasoactive molecules such as PGE2, astrocytes regulate local blood flow (functional hyperemia) and through the release of angiogenic signals induce tight junction proteins that form the blood brain barrier (BBB). Consequently, any condition that compromises the structure or function of the endfoot can cause impaired blood flow or impairments of the BBB. In a previous study using a model of familial Alzheimer disease (AD; hAPPJ202), we1 showed vascular amyloid deposits aggregating between the astrocytic endfeet and the vessel wall and such amyloid laden vessels showed an impaired ability to regulate vascular tone and blood flow upon stimulation. Preliminary data suggests that where amyloid deposits are present on vessels and endfeet displaced, focal breaches in the BBB occur. However, the causative role of vascular amyloid versus structural and functional changes of astrocytic endfeet in this context are not known. Indeed, while reduced blood flow and weakening of the BBB have been demonstrated with aging, the specific role of astrocytes in vessel health over the lifespan are largely unknown. We hypothesize that normal aging is associated with progressive dysfunction of astrocytic endfeet causing impairment in functional hyperemia and gradual weakening of the BBB. These agerelated impairments are accelerated in the AD brain as a function of amyloid being functionally “toxic” to astrocytes and/or pericytes. Here we propose to use two genetic mouse model of familial AD (hAPPJ202, APP233) with robust vascular amyloidosis1,4 and progressive gliosis1, and age matched control animals to study the specific role of astrocytes and pericytes to maintain vessel health and function during normal and pathological aging. No prior studies have examined specific functional impairments of astrocyte endfeet in normal aging compared to AD, and a possible specific gliotoxic effect of amyloid; two conceptually innovative ideas. State of the art chronic in vivo multi-photon imaging will be applied to well established transgenic mouse models of AD with vascular amyloidosis. Combined with novel cell-type specific genomics and proteomics, this proposal will shed light on astrocyte specific changes in gene and protein expression over the time course of AD (and normal aging) with specific analysis of gender differences.

脑血管的表面几乎完全被称为星形胶质细胞末端的星形胶质细胞突起覆盖。端脚的位置完美，可以与内皮血管壁相互作用，并且如果存在的话，周围的血管也可以与内皮血管壁相互作用。星形胶质细胞通过释放血管活性分子（如 PGE2）调节平滑肌或周细胞。血流（功能性充血）并通过释放血管生成信号诱导紧密连接蛋白形成血脑屏障（BBB）检查，任何损害血脑屏障结构或功能的情况。在之前的一项使用家族模型的研究中，足底可能会导致血流受损或血脑屏障受损。阿尔茨海默病（AD；hAPPJ202），we1显示血管淀粉样沉积物在星形细胞之间聚集足末和血管壁以及此类富含淀粉样蛋白的血管显示出调节血管张力的能力受损和刺激后的血流。初步数据表明淀粉样蛋白沉积物存在于血管上。然而，血管淀粉样蛋白的致病作用却是不同的。事实上，星形胶质细胞末端的结构和功能变化尚不清楚，同时血液减少。随着年龄的增长，血脑屏障的流动和减弱已被证明，星形胶质细胞在血管健康中的具体作用我们一直认为正常衰老与进行性功能障碍有关。星形细胞末足的损伤导致功能性充血受损和血脑屏障逐渐减弱，这些与年龄有关。由于淀粉样蛋白对 AD 大脑具有功能性“毒性”，AD 大脑中的损伤会加速。在这里，我们建议使用两种家族性 AD 的遗传小鼠模型（hAPPJ202、APP233）。与强血管淀粉样变性1,4和进行性神经胶质增生1，以及年龄匹配的对照动物来研究具体星形胶质细胞和周细胞在正常和病理性衰老过程中维持血管健康和功能的作用。先前没有研究检查星形胶质细胞末端足在正常衰老过程中与对照组相比的特定功能损伤。 AD，以及淀粉样蛋白可能具有的特定胶质毒性作用；这两个概念上的创新想法是长期存在的。体内多光子成像将应用于已建立的患有血管性 AD 的转基因小鼠模型结合新的细胞类型特异性基因组学和蛋白质组学，该提案将揭示淀粉样变性。随着AD（和正常衰老）的时间进程，星形胶质细胞基因和蛋白质表达的特异性变化具有特定的性别差异分析。