Spatial and Temporal Progression of Amyloid Angiopathy

描述（由申请方提供）：脑淀粉样血管病（CAA），即脑血管淀粉样蛋白（AH）的年龄相关性沉积，是出血性卒中的常见原因，是大多数阿尔茨海默病（AD）病例的伴随病理，也是抗All免疫治疗AD的不良反应的潜在原因。CAA在死后人脑中的研究受到无法随着疾病进展进行观察的限制。我们已经在CAA小鼠模型中使用了体内多光子显微镜来定义活动物中疾病的空间和时间进展。我们已经证明，脑血管AH沉积的发生是可预测的，具有容易测量的动力学，被动免疫治疗改变了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。因此，我们现在建议使用新的方法来确定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和血管平滑肌细胞的损伤。在具体目标#1中，我们将在小鼠模型中进行CAA进展的系列成像，并确定淀粉样蛋白沉积和血管壁损伤标志物之间的空间和时间关系。这个目标的目标是精确理解导致血管壁损伤的通路中的事件顺序。在具体目标#2中，我们将研究使用被动免疫和其他方法清除Afi可以中断或逆转CAA诱导的血管壁损伤变化。由于小鼠模型仅与人类疾病相关，因此在具体目标#3中，我们将确定我们验证的小鼠模型血管壁损伤标志物中的哪些也在人类CAA中发现。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的访问（包括散发性CAA，与APP突变相关的CAA，来自Aft疫苗的AN 1792试验的组织以及家族性英国和丹麦痴呆症）。从这些研究中，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）适合治疗干预的点;（3）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.