Spatial and Temporal Progression of Amyloid Angiopathy

描述（由申请人提供）：脑淀粉样血管病（CAA），与年龄相关的脑血管ft-淀粉样蛋白（AH）沉积，是出血性卒中的常见原因，是大多数阿尔茨海默病（AD）的伴随病理，也是AD抗all免疫治疗方法不良反应的潜在原因。由于无法随着疾病的进展进行观察，对死后人脑CAA的研究受到限制。我们在小鼠CAA模型中使用了体内多光子显微镜来确定活动物疾病的空间和时间进展。我们已经表明，脑血管AH沉积可预测地发生，并且易于测量动力学，被动免疫治疗改变CAA的进展，并可导致血管壁淀粉样蛋白沉积的清除。CAA的后果部分与血管壁破裂有关。基于这个原因，我们现在建议使用新的方法来定义阿里诱导的血管壁损伤的机制，包括氧化应激、基质金属蛋白酶和其他蛋白酶的激活以及血管平滑肌细胞的损伤。在Specific Aim #1中，我们将在小鼠模型中对CAA进展进行连续成像，并定义淀粉样蛋白沉积与血管壁损伤标志物之间的时空关系。这一目标的目标将是在导致血管壁损伤的途径事件序列的精确理解。在Specific Aim #2中，我们将检查哪些caa诱导的血管壁损伤改变可以通过使用被动免疫和其他方法清除Afi来中断或逆转。由于小鼠模型只与人类疾病相关，因此在Specific Aim #3中，我们将确定小鼠模型中哪些经过验证的血管壁损伤标记也存在于人类CAA中。我们将利用我们在CAA临床和神经病理学特征方面的专业知识，以及我们对广泛的人类样本（包括散发性CAA、与APP突变相关的CAA、来自Aft疫苗AN1792试验的组织以及英国和丹麦家族性痴呆）的获取。通过这些研究，我们将更清楚地了解(1)AIS沉积导致血管壁损伤和神经损伤的机制；(2)适合治疗干预的穴位；(3)在接受抗淀粉样蛋白治疗的阿尔茨海默病患者中与CAA相关的风险。

DESCRIPTION (provided by applicant): Cerebral amyloid angiopathy (CAA), the age-related deposition of cerebrovascular ft-amyloid (AH), is a common cause of hemorrhagic stroke, an accompanying pathology in most cases of Alzheimer disease (AD), and a potential cause of adverse responses to anti-All immunotherapeutic approaches to AD. Studies of CAA in the postmortem human brain are limited by the inability to make observations over time as the disease progresses. We have used in vivo multiphoton microscopy in mouse models of CAA to define the spatial and temporal progression of the disease in living animals. We have shown that cerebrovascular AH deposition occurs predictably with readily measured kinetics and that passive immunotherapy alters the progression of CAA and can lead to clearance of amyloid deposits from vessel walls. The consequences of CAA are associated in part with breakdown of the vessel wall. For this reason, we now propose to use novel methods to define the mechanisms that underlie Ali-induced vascular wall injury, including oxidative stress, activation of matrix metalloproteinases and other proteases and injury to vascular smooth muscle cells. In Specific Aim #1, we will perform serial imaging of CAA progression in mouse models and define the spatial and temporal relationship between amyloid deposition and markers of injury to the vessel wall. The goal of this aim will be a precise understanding of the sequence of events in the pathway that lead to vascular wall injury. In Specific Aim #2, we will examine which of the CAA-induced alterations in vessel wall injury can be interrupted or reversed by clearance of Afi using passive immunization and other methods. Because mouse models are only relevant in as much as they speak to human disease, in Specific Aim #3, we will determine which of our validated set of markers of vascular wall injury from mouse models are also found in human CAA. We will make use of our expertise in the clinical and neuropathologic characteristics of CAA and our access to a wide range of human samples (including sporadic CAA, CAA linked to APP mutations, tissue from the AN1792 trial of the Aft vaccine and familial British and Danish dementias. From these studies we will develop a clearer understanding of (1) mechanisms by which AIS deposition results in vascular wall injury and neurologic injury; (2) points suitable for therapeutic intervention; and (3) risks associated with the CAA in patients undergoing anti-amyloid therapies for Alzheimer disease.