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: 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
• 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' 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终足的星形胶质细胞过程所覆盖。星形细胞 端足被完美地定位以与内皮血管壁以及周围血管壁（如果存在的话）相互作用。 平滑肌或周细胞。通过释放血管活性分子，如PGE 2，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，任何损害组织的结构或功能的情况， 末端足可导致血流受损或BBB受损。在以前的一项研究中，使用了一种家庭模型， 阿尔茨海默病（AD; hAPPJ 202），我们1显示血管淀粉样沉积物聚集在星形胶质细胞之间， 终足和血管壁，以及这种淀粉样蛋白负载的血管显示出调节血管张力的能力受损 和血液流动。初步数据表明，血管上淀粉样蛋白沉积的地方 并且端足移位，BBB中出现局灶性破裂。然而，血管淀粉样蛋白与 在这种情况下星形胶质细胞终足的结构和功能变化是未知的。事实上，当血液减少时， 血脑屏障的流动和减弱已被证明与老化，星形胶质细胞在血管健康的具体作用， 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 星形胶质细胞终足的损伤导致功能性充血和BBB的逐渐减弱。这些与年龄有关的 由于淀粉样蛋白在功能上对AD脑具有“毒性”， 星形胶质细胞和/或周细胞。本研究采用两种遗传性AD小鼠模型（hAPPJ 202、APP 233）， 与年龄匹配的对照组动物进行比较，以研究 星形胶质细胞和周细胞在正常和病理老化期间维持血管健康和功能的作用。 以前的研究没有检查过正常老化中星形胶质细胞终足的特定功能损伤， AD和淀粉样蛋白可能的特异性神经胶质毒性作用;两个概念上的创新想法。最新技术水平， 体内多光子成像将应用于已建立的血管性AD转基因小鼠模型 淀粉样变性结合新的细胞类型特异性基因组学和蛋白质组学，这一建议将阐明 随着AD（和正常衰老）的时间进程，星形胶质细胞的基因和蛋白质表达发生特异性变化， 性别差异分析。