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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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 阿尔茨海默病（AD）是一种使人衰弱的慢性神经退行性疾病，其是阿尔茨海默病最常见的形式。 痴呆AD的病理生理学包括在整个脑组织中神经元和突触的进行性损失。 大脑皮质以及皮质下区域，并且以淀粉样蛋白β（Aβ）斑块的积聚为特征 以及遍布这些区域的含tau的神经元缠结病理。据报道， 与神经元和神经胶质细胞（实质斑块）相关，或与血管相关 （血管斑块称为脑淀粉样血管病[CAA]）。CAA在高达90%的AD患者中被发现， 并被认为导致血流受损、血管形态改变、炎症、微出血和 出血尽管CAA很重要，但对Aβ如何在血管周围沉积知之甚少。 有两个主要假设：第一，血管斑块是通过Aβ的异常分泌产生的， 内皮细胞和/或壁细胞。第二，血管斑块通过清除功能障碍而产生 Aβ。在这里，我们测试了一个新的假设：血管周围成纤维细胞分泌Aβ在CAA的产生。工作 我们的实验室已经确定血管周围成纤维细胞与AD患者的血管Aβ斑块密切相关， 死后组织我们还发现血管周围成纤维细胞强烈表达淀粉样蛋白， 前体蛋白（APP）和加工淀粉样蛋白的酶（BACE 1/2，PSEN 1）。在这里，我们将使用 条件性基因敲除方法，以确定成纤维细胞是否是分泌Aβ的关键细胞类型， 在充分表征的AD小鼠模型中产生CAA。我们还将利用单细胞测序， 检查血管周围成纤维细胞的细胞异质性和基因表达作为时间的函数， 小鼠AD模型。如果我们发现血管周围成纤维细胞是Aβ分泌的关键因素， 的CAA，那么这个分析将提供见解的机制，导致这种血管Aβ积累。 如果我们发现成纤维细胞分泌Aβ对于CAA的产生不是必需的，那么这一分析将提供 关于成纤维细胞在血管Aβ斑块形成过程中如何变化的重要信息， 是密切相关的。