权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10334548
负责人：
HARALD W SONTHEIMER
金额：
$ 48.58万
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/10334548
关键词：
Ablation 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 Gene Proteins Genes Genetic Genomics Gliosis Health Hippocampus (Brain)Hyperemia Impairment Lasers Light Longevity Magnetism Maintenance Modeling Mus Pathogenesis Pathologic Peptide Hydrolases Pericytes Positioning Attribute Process Proteins Proteome Proteomics Research Role Secondary to Senile Plaques Sex Differences 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.

脑血管表面几乎完全被称为终足的星形胶质突起覆盖。星形