Vascular breakdown in Alzheimers Disease with cerebrovascular disease

描述（由申请方提供）：微血管扩张和血管源性水肿是脑血管病（CBVD）和阿尔茨海默病（AD）中发生的病理现象。在CBVD中，这些可以发生在整个大脑中，但最常见的是皮质下。在AD中，它们通常发生在血管淀粉样蛋白沉积部位。考虑到CBVD和AD并不总是相互排斥的，而是经常共存，因此我们了解微血管扩张和血管源性水肿的机制非常重要。我们假设炎症介导的基质金属蛋白酶激活导致紧密连接蛋白和基底膜蛋白变性，导致血管渗漏，产生微血管扩张和/或血管源性水肿。 我们这项提议的目标是在淀粉样蛋白沉积的小鼠模型中模拟CBVD，以产生血管源性水肿和微出血，并确定MMP系统在其发病中的作用以及CBVD对淀粉样蛋白靶向治疗反应的影响。我们将评估炎症变化和MMP系统的激活作为这些异常的机制。重要的是，我们建议采集MR FLAIR和磁敏感加权（SWI）图像，以评估血管源性水肿和微出血以及研究过程中发生的任何其他脑部变化。在组织采集之前，我们将立即获取动脉自旋标记（ASL）扫描以测量脑灌注，从而能够比较微血管密度和脑健康。此外，我们将在给予Magnevist和G白蛋白造影剂后进行对比增强T1加权扫描，以评估血管渗漏。我们建议使用AAV和药理学试剂直接抑制MMP，或抑制被认为是增加MMP活性的炎症信号。我们还将检查试验中两种A？靶向治疗的疗效和副作用是否受到淀粉样蛋白沉积小鼠中CBVD存在的影响。 我们建议的总体目标是确定当我们在APP/PS1转基因小鼠中产生CBVD时CBVD病理学的时间过程，确定炎症和MMPs在微出血和血管源性水肿产生中的作用，并最终确定CBVD对A？靶向治疗的反应的影响。我们认为CBVD是AD的常见共病，影响AD的发病机制和治疗反应。

DESCRIPTION (provided by applicant): Microhemorrhages and vasogenic edema are pathological phenomena that occur in both cerebrovascular disease (CBVD) and Alzheimer's disease (AD). In CBVD these can occur throughout the brain, yet are most frequently subcortical. In AD they usually occur at sites of vascular amyloid deposition. Given that CBVD and AD are not always mutually exclusive but often co-exist it is important that we understand the mechanisms of microhemorrhages and vasogenic edema. We hypothesize that inflammatory-mediated activation of matrix metalloproteinases leads to degeneration of tight junction proteins and basement membrane proteins resulting in vascular leakage producing microhemorrhages and/or vasogenic edema. Our goal for this proposal is to model CBVD in mouse models of amyloid deposition to produce vasogenic edema and microhemorrhage and determine the role of the MMP system in their onset and the impact CBVD has on response to amyloid-targeted therapies. We will assess inflammatory changes and activation of the MMP systems as mechanisms for these abnormalities. Importantly, we propose to acquire MR FLAIR and Susceptibility Weighted (SWI) images to assess vasogenic edema and microhemorrhage as well as any other brain changes occurring through the course of the studies. Immediately prior to tissue harvest we will acquire arteral spin label (ASL) scans to measure brain perfusion and thus enable a comparison of the density of microhemorrhages and brain health. Additionally, we will acquire contrast enhanced T1-weighted scans following administration of Magnevist and Galbumin contrast agents to assess vascular leakage. We propose to use AAV and pharmacological agents to inhibit MMPs directly, or inhibit the inflammatory signals thought to be increasing MMP activity. We will also examine whether the efficacy and side-effect profile of two A¿- targeted therapies in trials are influenced by the presence of CBVD in amyloid-depositing mice. The overall goal of our proposal is to determine the time-course of CBVD pathology when we generate CBVD in APP/PS1 transgenic mice, determine the roles of inflammation and MMPs in the generation of microhemorrhage and vasogenic edema, and finally to establish the effect CBVD has on the response to A¿-targeted therapies. We believe that CBVD is common co- morbidity with AD that influences the pathogenesis of AD and response to therapy.