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Examining the role of perivascular fibroblasts in cerebral amyloid angiopathy during Alzheimers disease

检查血管周围成纤维细胞在阿尔茨海默病期间脑淀粉样血管病中的作用

基本信息

批准号：
9897476
负责人：
Richard Daneman
金额：
$ 19.69万
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：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9897476
关键词：
Abeta clearance Abeta synthesis Affect Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Arteries Autopsy Blood - brain barrier anatomy Blood Vessels Blood flow Brain Carotid Artery Ulcerating Plaque Cells Cerebral Amyloid Angiopathy Cerebral cortex Chronic Data Dementia Deposition Disease Endothelial Cells Enzymes Failure Fibroblasts Functional disorder Gene Expression Gene Expression Profile Generations Health Hemorrhage Heterogeneity Impairment Inflammation Intracranial Hemorrhages Lead LoxP-flanked allele Meninges Molecular Morphology Mus Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Partner in relationship Pathology Patients Population Process Production Reporter Reporting Resources Role Senile Plaques Stroke Synapses Testing Time Tissues Transgenic Mice Work abeta accumulation alpha secretase amyloid precursor protein processing arteriole beta-site APP cleaving enzyme 1 cell type conditional knockout dementia risk disorder control experimental study frontal lobe glymphatic system insight mouse model neuroinflammation neuron loss novel presenilin-1 response single cell sequencing single-cell RNA sequencing tau Proteins therapeutic target

项目摘要

ABSTRACT Alzheimer's disease (AD) is a debilitating, chronic neurodegenerative disease that is the most common form of dementia. The pathophysiology of AD includes the progressive loss of neurons and synapses throughout the cerebral cortex as well as subcortical regions, and is characterized by the buildup of amyloid-beta (Aβ) plaques and tau-containing neurofibrillary tangle pathologies throughout these regions. Aβ plaques have been reported to be associated with neuronal and glial cells (parenchymal plaques), or associated with blood vessels (vascular plaques termed cerebral amyloid angiopathy [CAA]). CAA is found in up to 90% of patients with AD, and is thought to lead to impaired blood flow, altered vascular morphology, inflammation, microbleeds and hemorrhage. Despite the importance of CAA, very little is known about how Aβ deposits around vessels. There are two main hypotheses: First, vascular plaques are generated through the aberrant secretion of Aβ by endothelial cells and/or mural cells. Second, vascular plaques are generated though dysfunction in clearance of Aβ. Here we test a novel hypothesis: perivascular fibroblasts secrete Aβ in the generation of CAA. Work in our lab has identified that perivascular fibroblasts are intimately associated with vascular Aβ plaques in AD postmortem tissue. We have also identified that that perivascular fibroblasts robustly express amyloid precursor protein (APP) and the enzymes that process amyloid (BACE1/2, PSEN1). Here, we will use a conditional knockout approach to determine whether fibroblasts are the key cell type that secretes Aβ in the generation of CAA in a well characterized mouse model of AD. We will also utilize single cell sequencing to examine the cellular heterogeneity and gene expression of the perivascular fibroblasts as a function of time in the mouse AD model. If we find that perivascular fibroblasts are key contributors to Aβ secretion in the buildup of CAA, then this analysis will give insights into to the mechanism that leads to this vascular Aβ accumulation. If we find that fibroblast secretion of Aβ is not necessary for the generation of CAA, this analysis will provide vital information about how the fibroblasts change during the formation of vascular Aβ plaques, with which they are intimately associated.

摘要