Spatial and temporal progression of amyloid angiopathy

淀粉样血管病的空间和时间进展

• 批准号: 6789393
• 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 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6789393
• 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(申请人提供)：淀粉样蛋白沉积在脑血管中(脑淀粉样血管病变，CAA)是老年人的一种常见情况，与出血性和缺血性中风有关。CAA也是理解阿尔茨海默病S病发病机制的潜在重要模型，阿尔茨海默病是中枢神经系统的另一种主要的β淀粉样变性。在马萨诸塞州总医院的阿尔茨海默病研究单位，我们使用临床、神经病理学和遗传学方法来定义CAA涉及的致病步骤。然而，这些研究受到死后脑组织的静态性质和单一脑部切片的二维性质的限制。目前的提议试图通过使用多光子共聚焦显微镜观察转基因小鼠随时间的发展来观察CAA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，从而突破这些限制。我们将使用这些技术来检测1)血管中淀粉样蛋白的沉积；2)充满淀粉样蛋白的血管壁的破坏；以及3)抗淀粉样蛋白免疫治疗的反应。我们将测试Abeta最初是否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的时间表，从A13种物质的首次沉积到淀粉样蛋白的形成、平滑肌细胞的丧失以及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有害影响。研究将在双转基因突变淀粉样前体蛋白和早老素-1的小鼠身上进行，这些小鼠最早在6个月大的时候就表现出可检测到的CAA。对淀粉样蛋白沉积和血管破裂的三维结构的平行研究将在从收集的CAA病例中提取的人体组织上进行，包括独特的爱荷华州形式的家族性CAA。这些研究的成功完成将勾勒出CAA启动、传播和血管损伤所涉及的途径，并确定对这种目前无法治疗的疾病进行特异性免疫治疗的可行性。