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: 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
• 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' 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; 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

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星形细胞突起所覆盖，这种突起称为终足。星形细胞 末端足处于与内皮血管壁相互作用的完美位置，如果存在的话，还可以与周围环境相互作用。 平滑的肌肉或周细胞。通过释放PGE2等血管活性分子，星形胶质细胞调节局部 血流(功能性充血)和通过血管生成信号的释放诱导紧密连接蛋白 形成血脑屏障(BBB)。因此，任何危及 内足会导致血液流动障碍或血脑屏障受损。在之前的一项研究中，使用了家族性 阿尔茨海默病(AD；hAPPJ202)，我们1显示血管淀粉样沉积聚集在星形细胞之间 终足、血管壁和这种淀粉样蛋白血管显示出调节血管张力的能力受损。 以及刺激下的血液流动。初步数据表明，在血管上存在淀粉样沉积的地方 和后脚移位，血脑屏障局部破裂。然而，血管淀粉样蛋白的致病作用与 在这种情况下，星形细胞终足的结构和功能变化尚不清楚。的确，虽然减少了血液 随着年龄的增长，已经证实了血脑屏障的流动和减弱，星形胶质细胞在血管健康中的特殊作用 寿命长短在很大程度上是未知的。我们假设正常衰老与进行性功能障碍有关 星形细胞终足导致功能性充血的损害和血脑屏障的逐渐减弱。这些与年龄有关的人 阿尔茨海默病大脑中的损伤是由于淀粉样蛋白在功能上“有毒”到 星形胶质细胞和/或周细胞。在这里，我们建议使用两种遗传性AD小鼠模型(hAPPJ202，APP233) 用健壮的血管淀粉样变性1，4和进行性胶质变性1，和年龄匹配的对照组动物研究特异性 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。 以前没有研究过星形胶质细胞终足在正常衰老时的特定功能损害。 AD，以及淀粉样蛋白可能的特定神经胶质毒性作用；两个概念上的创新想法。长期处于最先进的状态 体内多光子成像将应用于已建立的阿尔茨海默病转基因小鼠血管模型 淀粉样变性。结合新的细胞类型特定基因组学和蛋白质组学，这一建议将阐明 星形胶质细胞在阿尔茨海默病(和正常衰老)过程中特异性基因和蛋白表达的变化 性别差异分析。