Role of Microvascular Lesions in Alzheimer's Disease

描述（申请人提供）：近年来，脑微血管疾病已被确定为阿尔茨海默病的重要组成部分。由于缺乏微血管疾病的动物模型，这两种疾病之间相互作用的机制仍不清楚。这项工作旨在研究微血管损伤与阿尔茨海默病的主要特征Ap积累之间的相互关系。这项工作建立在临床观察的基础上，阿尔茨海默病中痴呆的严重程度通常与血管疾病的存在有关。我们使用新颖的光学工具在阿尔茨海默病转基因小鼠模型中诱导微血管病变，然后对由此产生的病理进展进行成像。我们的损伤技术，飞秒激光消融，可以破坏皮质表面下500分钟深处的单个微血管。该研究包括多种类型的微血管病变，包括出血、缺血性闭塞和短暂性渗漏，所有这些都可能导致疾病进展。双光子激发荧光显微镜用于成像淀粉样斑块的发展，并测量微血管的血流和渗漏。这允许对微血管病变和淀粉样斑块进行延时研究。死后用A(3抗体标记将用于进一步阐明微血管病变对Ap积累的影响。在Aim 1中，我们测试了微血管凝块和出血是否会在血管树的不同位置触发淀粉样斑块的快速形成。在目标2中，我们询问生命早期的血管病变是否会导致后来的斑块易感性。在最终目的中，我们确定由血管病变播种的斑块相对于不同细胞类型的位置，并确定炎症或活性氧是否是通过共定位研究的因素。此外，我们使用组织学和免疫组织学分析来鉴定受影响的细胞并绘制Ap积累图。我们的初步研究结果预测，微血管凝块的存在将加速局部Ap斑块的沉积。这些数据提示微血管病变可能在阿尔茨海默病的发病机制中起重要作用。相关性~阿尔茨海默病是老年痴呆症最常见的病因。在临床上，阿尔茨海默病经常与血管疾病纠缠在一起，这表明这两种疾病是密切相关的。对许多病人来说，成功的治疗必须同时解决这两个方面。这项工作调查了这两种情况是如何相互恶化的，并将有助于确定预防痴呆症的策略。

DESCRIPTION (provided by applicant): Recently, cerebral microvessel disease has been identified as an important component of Alzheimer's disease. The mechanism of interaction between the diseases is still unclear in part because animal models of microvascular disease are lacking. The proposed work studies the interrelationship between microvascular damage and the accumulation of Ap, the dominant characteristic of Alzheimer's disease. This work builds on the clinical observation that the severity of dementia in Alzheimer's disease is often related to the presence of vascular disease. We use novel optical tools to induce microvascular lesions in transgenic mouse models of Alzheimer's disease and then image the progression of the resulting pathology. Our lesioning technique, femtosecond laser ablation, can disrupt individual microvessels as deep as 500 pm beneath the cortical surface. The study includes multiple types of microvascular lesions, including hemorrhages, ischemic occlusions and transient leakages, all of which potentially contribute to disease progression. Two-photon excited fluorescence microscopy is used to image amyloid plaque development and to measure blood flow and leakage in the microvasculature. This allows time-lapsed study of both the microvascular lesion and amyloid plaque. Post-mortem labeling with A(3 antibodies will be used to further elucidate the impact of the microvascular lesion on Ap accumulation. In Aim 1, we test whether microvascular clots and hemorrhages trigger rapid amyloid plaque formation at different locations in the vascular tree. In Aim 2, we ask if vascular lesions earlier in life can induce a predisposition to plaques later. In the final aim, we determine where plaques that are seeded by vascular lesions are relative to different cell types and determine whether inflammation or reactive oxygen species are factors through colocalization studies. In addition, we use histological and immunohistological assays to identify the affected cells and map the Ap accumulation. Our preliminary findings predict that the presence of a microvascular clot will accelerate the local deposition of Ap plaques. These data suggest that microvascular lesions could play an important role in Alzheimer's disease pathogenesis. Relevance ~ Alzheimer's disease is the most common cause of dementia in the elderly. Clinically, Alzheimer's disease is often entangled with vascular disease, suggesting that the two diseases are intimately interrelated. In many patients, sucessful treatment will have to address both aspects. This work investigates how the two conditions might worsen each other and will help identify strategies for preventing dementia.