Role of Microvascular Lesions in Alzheimer's Disease

描述(申请人提供)：最近，脑微血管疾病已被确认为阿尔茨海默病的重要组成部分。这些疾病之间相互作用的机制仍不清楚，部分原因是缺乏微血管疾病的动物模型。这项拟议的工作研究了微血管损伤和AP积聚之间的相互关系，AP是阿尔茨海默病的主要特征。这项工作建立在临床观察的基础上，即阿尔茨海默病的痴呆症的严重程度通常与血管疾病的存在有关。我们使用新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损伤，然后成像由此产生的病理进展。我们的损伤技术，飞秒激光消融，可以破坏皮质表面下深达500 PM的单个微血管。这项研究包括多种类型的微血管病变，包括出血、缺血闭塞和一过性渗漏，所有这些都可能导致疾病的进展。双光子激发荧光显微镜被用来成像淀粉样斑块的发展和测量微血管中的血流量和渗漏。这使得对微血管病变和淀粉样斑块的时间推移研究成为可能。A(3)抗体的死后标记将被用来进一步阐明微血管病变对AP聚集的影响。在目标1中，我们测试微血管凝块和出血是否会在血管树的不同位置引发快速的淀粉样斑块形成。在目标2中，我们询问生命早期的血管损伤是否会在以后诱发斑块的易感性。在最终目标中，我们确定由血管病变种植的斑块与不同细胞类型的关系，并通过共同定位研究确定炎症或活性氧是影响因素。此外，我们使用组织学和免疫组织学方法来识别受影响的细胞，并绘制AP聚集的图谱。我们的初步发现预测，微血管凝块的存在将加速AP斑块的局部沉积。这些数据表明，微血管病变可能在阿尔茨海默病的发病机制中发挥重要作用。相关：阿尔茨海默病是导致老年人痴呆症的最常见原因。临床上，阿尔茨海默病往往与血管疾病纠缠在一起，这表明这两种疾病是密切相关的。在许多患者中，成功的治疗必须解决这两个方面。这项工作调查了这两种情况如何相互恶化，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.