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

• 批准号: 10438950
• 负责人: HARALD W SONTHEIMER
• 金额: $ 39.82万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 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/10438950
• 关键词: Ablation; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' 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

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Endfeet的星形胶质细胞过程覆盖。星形细胞 Endfeet完全可以与内皮容器墙相互作用，在存在周围的地方 光滑的肌肉或周细胞。通过释放血管活性分子，例如PGE2，星形胶质细胞调节局部 血流（功能性充血）和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）。因此，任何损害该结构或功能的条件 末脚会导致血流受损或BBB的损害。在先前使用家庭模型的研究中 阿尔茨海默氏病（AD; HAPPJ202），WE1显示出淀粉细胞之间聚集的血管淀粉样蛋白沉积物 端露室和容器壁以及这种淀粉样蛋白负载的容器表现出调节血管张力的能力受损 刺激时的血液流动。初步数据表明，在容器上存在淀粉样蛋白沉积物 Endfeet流离失所，BBB中发生了局灶性断裂。但是，血管淀粉样蛋白与 在这种情况下，星形胶质细胞终端的结构和功能变化尚不清楚。确实，虽然血液减少 通过衰老证明了BBB的流量和弱化，星形胶质细胞在血管健康中的特定作用 在整个生命周期中，基本上未知。我们假设正常衰老与进行性功能障碍有关 星形胶质细胞终身导致功能性充血和BBB级弱弱化的损害。这些年龄有关 在AD大脑中，损伤是由于淀粉样蛋白在功能上“有毒”的函数加速的 星形胶质细胞和/或周细胞。在这里，我们建议使用两种遗传鼠标模型的家庭AD模型（HappJ202，App233） 具有强大的血管淀粉样变性1,4和进行性神经胶质病1，并与对照动物相匹配，以研究特定 星形胶质细胞和周细胞在正常和病理衰老期间保持血管健康和功能的作用。 与先前的研究相比 AD，以及淀粉样蛋白的可能特异性神经毒性作用；两个概念上创新的思想。慢性病状态 体内多光子成像将应用于具有血管的AD的良好转基因小鼠模型 淀粉样变性。结合新颖的细胞类型特异性基因组学和蛋白质组学，该建议将揭示 在AD（和正常衰老）的时间过程中，星形胶质细胞特异性变化具有特定的AD（和正常衰老） 分析性别差异。