Role of Microvascular Lesions in Alzheimer's Disease

描述（由申请人提供）：最近，脑微血管疾病已被确定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。拟议的工作研究微血管损伤和Ap积累之间的相互关系，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。我们使用新的光学工具来诱导阿尔茨海默病转基因小鼠模型的微血管病变，然后成像所产生的病理学的进展。我们的损伤技术，飞秒激光消融，可以破坏皮质表面下500 pm深的单个微血管。该研究包括多种类型的微血管病变，包括闭塞、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，并测量微血管系统中的血流和渗漏。这允许对微血管病变和淀粉样斑块进行时间推移研究。用A β抗体进行死后标记将用于进一步阐明微血管病变对A β蓄积的影响。在目标1中，我们测试微血管凝块和血管扩张是否在血管树的不同位置触发快速淀粉样斑块形成。在目标2中，我们询问生命早期的血管病变是否会诱发日后斑块的易感性。在最终的目标中，我们确定由血管病变接种的斑块相对于不同细胞类型的位置，并通过共定位研究确定炎症或活性氧是否是因素。此外，我们使用组织学和免疫组织学测定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沉积的Ap斑块。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。阿尔茨海默病是老年痴呆症最常见的原因。在临床上，阿尔茨海默病经常与血管疾病纠缠在一起，这表明这两种疾病密切相关。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.