Vascular breakdown in Alzheimers Disease with cerebrovascular disease

描述(申请人提供)：微量出血和血管源性水肿是脑血管疾病(CBVD)和阿尔茨海默病(AD)中都会出现的病理现象。在CBVD中，这些可以发生在整个大脑，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的部位。鉴于CBVD和AD并不总是相互排斥的，但往往是共存的，我们理解微出血和血管源性水肿的机制是很重要的。我们假设炎症介导的基质金属蛋白酶的激活导致紧密连接蛋白和基底膜蛋白的退化，导致血管渗漏，产生微出血和/或血管源性水肿。我们这项建议的目标是在淀粉样蛋白沉积的小鼠模型中建立CBVD模型，以产生血管源性水肿和微出血，并确定基质金属蛋白酶系统在其发生中的作用以及CBVD对淀粉样蛋白靶向治疗的反应的影响。我们将评估炎症变化和基质金属蛋白酶系统的激活作为这些异常的机制。重要的是，我们建议获取MR FLAIR和敏感性加权(SWI)图像来评估血管源性水肿和微出血以及在研究过程中发生的任何其他脑变化。在组织采集之前，我们将获得动脉自旋标记(ASL)扫描，以测量脑血流，从而能够比较微出血的密度和脑健康。此外，我们将在注射Magnevist和白蛋白造影剂后获得增强的T1加权扫描，以评估血管渗漏。我们建议使用AAV和药理学药物直接抑制MMPs，或抑制被认为增加MMPs活性的炎症信号。我们还将检查试验中两种A？靶向疗法的疗效和副作用是否受到淀粉样蛋白沉积小鼠CBVD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病理的时间进程，确定炎症和MMPs在微出血和血管源性水肿产生中的作用，最后确定CBVD对Aβ靶向治疗的反应的影响。我们认为，CBVD是AD常见的并存疾病，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.