Spatial and Temporal Progression of Amyloid Angiopathy

淀粉样血管病的空间和时间进展

• 批准号: 7617178
• 负责人: MATTHEW P FROSCH
• 金额: $ 41万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617178
• 关键词: AN-1792; Affect; Alzheimer' s Disease; Amyloid; Amyloid deposition; Animal Model; Animals; Antibodies; Apoptosis; Arteries; Autopsy; Basement membrane; Blood Vessels; Brain; Brain hemorrhage; British; Cell Shape; Cell physiology; Cells; Cerebral Amyloid Angiopathy; Characteristics; Clinical; Clinical Trials; Dementia; Deposition; Development; Disease; Disease Progression; Event; Familial Dementias; Functional disorder; Gelatinase B; General Population; Generations; Goals; Hemorrhage; Human; Image; Immunotherapeutic agent; Immunotherapy; Inflammation; Inflammatory; Injury; Kinetics; Lead; Life; Link; Lobar; Matrix Metalloproteinases; Measures; Methods; Microscopy; Molecular; Mutation; Neurologic; Oxidative Stress; Passive Immunization; Passive Immunotherapy; Pathology; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Phase; Preventive; Process; Recovery; Recurrence; Research Personnel; Risk; Sampling; Smooth Muscle Myocytes; Sporadic Cerebral Amyloid Angiopathy; Stroke; Therapeutic Intervention; Time; Tissues; Vaccines; Validation; age related; cell injury; cerebrovascular; human disease; human tissue; immune clearance; in vivo; injured; insight; mouse model; novel; programs; response

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.

描述（由申请人提供）：脑淀粉样血管病 (CAA) 是脑血管 ft-淀粉样蛋白 (AH) 与年龄相关的沉积，是出血性中风的常见原因，是大多数阿尔茨海默病 (AD) 病例的伴随病理，也是对抗 All 免疫治疗 AD 方法产生不良反应的潜在原因。对死后人脑中 CAA 的研究受到限制，因为无法随着疾病的进展进行观察。我们在 CAA 小鼠模型中使用体内多光子显微镜来定义活体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，其动力学易于测量，并且被动免疫疗法可以改变 CAA 的进展，并可以导致淀粉样沉积物从血管壁上清除。 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。在具体目标 #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和血管壁损伤标志物之间的空间和时间关系。这一目标的目标是准确理解导致血管壁损伤的途径中的事件顺序。在具体目标 #2 中，我们将研究哪些 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。由于小鼠模型仅与人类疾病相关，因此在具体目标 #3 中，我们将确定哪些来自小鼠模型的经过验证的血管壁损伤标记物也存在于人类 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获得的广泛人类样本（包括散发性 CAA、与 APP 突变相关的 CAA、Aft 疫苗 AN1792 试验的组织以及英国和丹麦家族性痴呆）。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) 接受抗淀粉样蛋白治疗阿尔茨海默病的患者中与 CAA 相关的风险。