THE ROLE OF A-BETA SPECIES IN VASCULAR SMOOTH MUSCLE CELL AND CEREBRAL ARTERIOLE

A-β 物种在血管平滑肌细胞和脑小动脉中的作用

• 批准号: 8606781
• 负责人: GREGORY J ZIPFEL
• 金额: $ 32.92万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606781
• 关键词: Affect; Alzheimer' s Disease; Antibodies; Apolipoprotein E; Applications Grants; Asses; Binding; Blood Vessels; Brain; Brain Infarction; Cause of Death; Cell Culture Techniques; Cell Surface Receptors; Cell physiology; Cerebral Amyloid Angiopathy; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Data; Dementia; Deposition; Endothelial Cells; Functional disorder; Future; Genetic; Genetically Engineered Mouse; Goals; Grant; Immunotherapy; Impaired cognition; Impairment; In Vitro; Infarction; LDL-Receptor Related Protein 1; Link; Mediating; Memory; Methods; Mitochondria; Molecular; Mus; NADPH Oxidase; Outcome; Oxidative Stress; Pathology; Pathway interactions; Patients; Phenotype; Play; Predisposing Factor; Predisposition; Property; Reactive Oxygen Species; Research Personnel; Risk; Risk Factors; Role; Smooth Muscle Myocytes; Staging; Stroke; Testing; Tg2576; Therapeutic; Transgenic Mice; United States; Vascular Endothelial Cell; aged; amyloid peptide; arteriole; base; cerebrovascular; effective therapy; heparanase; heparin proteoglycan; improved; in vivo; monomer; peptide A; pre-clinical; prevent; public health relevance; research study; therapeutic development; therapy development

DESCRIPTION (provided by applicant): The role of A¿ species in vascular smooth muscle cell and cerebral arteriole dysfunction. Alzheimer's Disease (AD) is the leading cause of dementia; yet no therapy exists to slow or stop its progression. Recently, cerebrovascular (CV) pathology has been identified as a strong contributor to AD. Two key observations suggest that amyloid-¿ peptide (A¿) may play a role by either causing or increasing the susceptibility to cerebral ischemia. First, cerebral blood flow (CBF) is reduced in early stages of AD, and the reactivity of cerebral blood vessels is impaired - both of which have been linked to the vasoactive properties of A¿. Second, most AD patients develop A¿ deposits not only in brain but also in vessels - a condition known as cerebral amyloid angiopathy (CAA). CAA is a powerful risk factor for brain infarction and dementia, and is associated with severe CV dysfunction. A2 exists in several forms including soluble monomers (such as A¿40 and A¿42), soluble oligomers (toxic intermediate species), and insoluble fibrils (principle component of CAA). The former (primarily A¿40) and the latter (fibrillar A2 in the form of CAA) have been shown to powerfully alter CV function, while the vascular effects of A2 oligomers are not known. Our preliminary data suggest that the manner and extent to which monomeric A2 vs. fibrillar A2 cause CV dysfunction is different. We find that A¿ monomers cause a hyper-contractile vascular phenotype that is due to endothelial cell (EC) and vascular smooth muscle cell (VSMC) dysfunction that is mediated via reactive oxygen species (ROS), while A¿ fibrils in the form of CAA cause a hypo-contractile vascular phenotype that is primarily due to VSMC dysfunction that is mediated via ROS. We also identified a previously unrecognized contribution of ROS to CAA formation. The long-term objective of the proposed project is to test the central hypothesis that A¿ species powerfully and adversely affect the cerebral circulation by inducing VSMC-mediated arteriole dysfunction via an ROS- mediated pathway. The specific aims are 1) to determine whether A¿ species cause differential CV effects (hyper- vs. hypo-contractile impairment); 2) to determine the ROS pathways by which A¿ species cause VSMC and cerebral arteriole dysfunction; and 3) to determine the manner and extent to which ROS contribute to CAA formation, and to assess the functional benefits of reducing CAA via anti-ROS strategies. Methods used will include a) in vitro assessment of VSMC function after application of exogenous A¿ species; b) in vivo assessment of cerebral arteriole function in transgenic mice producing endogenous A¿ species; c) immunotherapy with anti-A¿ antibodies that bind A¿40, A¿42, A¿ oligomers, and/or A¿ fibrils; d) pharmacologic and genetic inhibition of NADPH oxidase; d) pharmacologic and genetic inhibition of the A2-binding cell surface receptors, LRP1 and HSPGs; and e) quantitation of CAA, A¿40, A¿42, APP, and ApoE. If successful, these studies will result in an improved understanding of the mechanisms underlying A¿-induced CV deficits and CAA formation. This will likely facilitate development of therapies targeting A¿ and its downstream effectors, which may ultimately improve the outcome of patients with AD, CAA, or both.

描述（由应用提供）：A种在血管平滑肌细胞和脑动物功能障碍中的作用。阿尔茨海默氏病（AD）是痴呆症的主要原因。然而，没有治疗可以放慢或停止其进展。最近，脑血管（CV）病理学​​已被确定为AD的有力贡献者。两个关键的观察结果表明，淀粉样蛋白肽（a。）可以通过引起或增加对脑缺血的敏感性发挥作用。首先，在AD的早期阶段降低了脑血流（CBF），并且脑血管的反应性受损 - 两者都与A?…的血管活性特性有关。其次，大多数AD患者不仅在大脑中，而且在Vissels中都会产生A的沉积物 - 这种疾病被称为脑淀粉样血管病（CAA）。 CAA是大脑梗塞和痴呆症的强大危险因素，并且与严重的CV功能障碍有关。 A2以几种形式存在，包括固体单体（例如A¿40和A€42），可溶性低聚物（有毒中间物种）和不溶性原纤维（CAA的原理）。前者（主要是A€40）和后者（Fibrillar）。 A2以CAA的形式显示出有力地改变CV功能，而A2低聚物的血管效应尚不清楚。我们的初步数据表明，单体A2与原纤维A2导致CV功能障碍的方式和程度不同。我们发现，单体会引起超收集的血管表型，该表型是由于内皮细胞（EC）和血管平滑肌细胞（VSMC）功能障碍，该功能是通过反应性氧（ROS）介导的，而CAA形式的fibrils以CAA形式引起的纤维均具有下降的血管型，从而导致iS iSPARIDES型均与ROSC相关。我们还确定了ROS对CAA形成的先前未识别的贡献。拟议项目的长期目标是测试中心假设，即通过通过ROS-介导的途径诱导VSMC介导的小动脉功能障碍，强大而不利地影响大脑循环。具体目的是1）确定一种物种是否引起差异性简历效应（超额收缩损伤）； 2）确定A域引起VSMC和脑动物功能障碍的ROS途径； 3）确定ROS对CAA形成的贡献的方式和程度，并评估通过反ROS策略减少CAA的功能益处。所使用的方法将包括a）应用外源性A农业后对VSMC功能的体外评估； b）在产生内源性a农的转基因小鼠中脑小鼠脑动物功能的体内评估； c）抗A抗体的免疫疗法结合A a a a a a a foLIS和/或纤维的抗体； d）NADPH氧化酶的药理和遗传抑制； d）A2结合细胞表面受体LRP1和HSPG的药理和遗传抑制； e）CAA，a¿40，a¿42，应用和apoe的定量。如果成功，这些研究将提高人们对诱导的简历定义和CAA形成的机制的理解。这可能会促进针对A及其下游影响的疗法的发展，这最终可能改善AD，CAA或两者兼而有之的疗法。