Spatial and temporal progression of amyloid angiopathy

描述（由申请人提供）：脑血管中淀粉样蛋白沉积（脑淀粉样血管病，CAA）是老年人出血性和缺血性中风的常见疾病。CAA也是了解阿尔茨海默病发病机制的潜在重要模型，阿尔茨海默病是另一种主要的中枢神经系统β -淀粉样变性。在马萨诸塞州总医院的阿尔茨海默病研究部门，我们使用临床、神经病理学和遗传学方法来确定CAA中涉及的致病步骤。然而，这些研究受到死后脑组织的静态性质和单个脑切片的二维性质的限制。目前的建议旨在通过使用多光子共聚焦显微镜观察转基因小鼠CAA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，从而突破这些限制。我们将使用这些技术来检查淀粉样蛋白在血管中的沉积过程；2)满载淀粉样蛋白的血管壁破裂；3)抗淀粉样蛋白免疫治疗反应。我们将测试β是否最初沉积在血管分枝点附近，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的时间线，从A13种的首次沉积到淀粉样蛋白的形成，平滑肌细胞的损失以及随后的血管病变变化。我们将确定抗β治疗是否对血管有潜在的有害影响。研究将在突变淀粉样蛋白前体蛋白和早老素- 1双转基因小鼠身上进行，这些小鼠在6个月大时就能检测到CAA。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中进行，包括独特的爱荷华州家族CAA。这些研究的成功完成将描述CAA起始、传播和血管损伤的相关途径，并确定针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。

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.