Spatial and temporal progression of amyloid angiopathy

描述（由申请人提供）：淀粉样蛋白在脑血管中的沉积（脑淀粉样血管病，CAA）是老年人中与出血性和缺血性中风相关的常见病症。 CAA 也是了解阿尔茨海默氏病（中枢神经系统的另一种主要 β-淀粉样变性病）发病机制的潜在重要模型。在马萨诸塞州总医院阿尔茨海默病研究室，我们使用临床、神经病理学和遗传学方法来定义 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。目前的提案旨在通过使用多光子共聚焦显微镜来观察转基因小鼠中 CAA 随着时间的推移的发展情况，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，从而超越这些限制。我们将使用这些技术来检查 1) 淀粉样蛋白在血管中沉积的过程； 2) 富含淀粉样蛋白的血管壁破裂； 3)对抗淀粉样蛋白免疫疗法的反应。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血管上。我们将生成 CAA 的时间线，从 A13 物质的首次沉积到淀粉样蛋白的形成、平滑肌细胞的损失以及随后的血管病变变化。我们将确定抗 Abeta 疗法是否对血管有潜在的有害影响。研究将对突变淀粉样前体蛋白和早老蛋白-1 的双转基因小鼠进行，这些小鼠在 6 个月大时就表现出可检测到的 CAA。将从收集的 CAA 病例（包括爱荷华州特有的家族性 CAA 病例）中获取的人体组织对淀粉样蛋白沉积和血管破裂的三维结构进行并行研究。这些研究的成功完成将描绘出参与 CAA 启动、传播和血管损伤的途径，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.