Spatial and temporal progression of amyloid angiopathy

淀粉样血管病的空间和时间进展

• 批准号: 6934575
• 负责人: MATTHEW P FROSCH
• 金额: $ 34.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6934575
• 关键词: Alzheimer' s disease; aging; amyloid proteins; amyloidosis; cerebral cortex; cerebral hemorrhage; cerebral ischemia /hypoxia; clinical research; confocal scanning microscopy; genetically modified animals; human tissue; laboratory mouse; neuritic plaques; neuropathology; pathologic process; presenilin; vascular smooth muscle

DESCRIPTION (provided by applicant): Deposition of amyloid in cerebral blood vessels (cerebral amyloid angiopathy, CAA) is a common condition in the elderly associated with both hemorrhagic and ischemic strokes. CAA is also a potentially important model for understanding the pathogenesis of Alzheimer' s disease, the other major beta-amyloidosis of the central nervous system. At the Alzheimer Research Unit at Massachusetts General Hospital, we have used clinical, neuropathological, and genetic approaches to define the pathogenic steps involved in CAA. These studies have been limited, however, by the static nature of post-mortem brain tissue and the two-dimensional nature of single brain sections. The current proposal seeks to move beyond these limitations by using multi-photon confocal microscopy to observe the development of CAA in transgenic mice over time, and by using multi-photon microscopy and computer-aided image reconstruction to analyze the three-dimensional structure of affected blood vessels. We will use these techniques to examine the processes of 1) amyloid deposition in vessels; 2) breakdown of the amyloid-laden vessel wall; and 3) response to anti-amyloid immunotherapy. We will test whether Abeta initially deposits near vessel branchpoints, whether vessel amyloid affects the deposition of parenchymal amyloid, and whether amyloid deposits preferentially on specific vessels. We will generate a timeline of CAA, from the first deposition of A13 species through formation of amyloid, loss of smooth muscle cells and subsequent vasculopathic changes. We will determine whether there are potential detrimental effects to vessels by anti-Abeta therapies. Studies will be performed on mice doubly transgenic for mutant amyloid precursor protein and presenilin- 1, mice that demonstrate detectable CAA at ages as early as six months. Parallel studies on the three-dimensional structure of amyloid deposition and vessel breakdown will be performed on human tissue taken from collected cases of CAA, including the unique Iowa form of familial CAA. Successful completion of these studies will delineate the pathways involved in CAA initiation, propagation, and vessel damage, as well as determine the feasibility of specific immunotherapy for this currently untreatable disorder.

描述（由申请人提供）：脑血管中淀粉样蛋白沉积（脑淀粉样蛋白血管病，CAA）是老年人中与出血性和缺血性卒中相关的常见疾病。CAA也是了解阿尔茨海默病（中枢神经系统的另一种主要β-淀粉样变性）发病机制的潜在重要模型。在马萨诸塞州综合医院的阿尔茨海默病研究中心，我们使用临床、神经病理学和遗传学方法来确定CAA的致病步骤。然而，这些研究受到死后脑组织的静态性质和单个脑切片的二维性质的限制。目前的建议试图超越这些限制，通过使用多光子共聚焦显微镜观察CAA在转基因小鼠中随时间的发展，并通过使用多光子显微镜和计算机辅助图像重建来分析受影响血管的三维结构。我们将使用这些技术来检查以下过程：1）血管中淀粉样蛋白沉积; 2）载有淀粉样蛋白的血管壁破裂; 3）对抗淀粉样蛋白免疫治疗的反应。我们将测试Abeta是否最初沉积在血管分支点附近，血管淀粉样蛋白是否影响实质淀粉样蛋白的沉积，以及淀粉样蛋白是否优先沉积在特定的血管上。我们将生成CAA的时间轴，从A13物质的首次沉积到淀粉样蛋白的形成、平滑肌细胞的损失和随后的血管病变变化。我们将确定抗Abeta治疗是否对血管有潜在的不利影响。研究将在突变淀粉样前体蛋白和早老素-1的双转基因小鼠上进行，这些小鼠在早至6个月的年龄时就表现出可检测的CAA。将对收集的CAA病例（包括独特的爱荷华州家族性CAA）的人体组织进行淀粉样蛋白沉积和血管破裂三维结构的平行研究。这些研究的成功完成将描绘CAA启动，传播和血管损伤所涉及的途径，以及确定这种目前无法治疗的疾病的特异性免疫治疗的可行性。