PLATELET AND THE CEREBROVASCULATURE IN AB DEPOSITION

AB 沉积中的血小板和脑血管

• 批准号: 2892461
• 负责人: THERESA A DAVIES
• 金额: $ 22.89万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-10 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2892461
• 关键词: Alzheimer's disease; amyloid proteins; apolipoprotein E; blood brain barrier; cell cell interaction; enzyme activity; human tissue; metalloendopeptidases; neuritic plaques; platelets; protein isoforms; protein transport; serine proteinases; tissue /cell culture; vascular endothelium; vascular smooth muscle

DESCRIPTION: Autopsies of Alzheimer's disease (AD) patients indicate the presence of organized deposits of B amyloid (AB) surrounding the microvasculature. These deposits are postulated to originate from amyloid precursor protein (APP) fragments released by activated platelets; the mechanism of this deposition found in patients with Alzheimer's disease but not in controls remains unclear. To date, it has not been shown whether APP fragments originating from platelets are capable of traversing the blood-brain barrier (BBB), and of then contributing to neural AB deposits. We have demonstrated the existence of an APP processing defect in platelets from patients with Alzheimer's disease leading to the retention of APP on the surface of activated platelets. The APP processing defect may be related to Aa plaque deposition in the cerebral vasculature. We have developed a model system, utilizing platelets and endothelial cells (EC), and have shown that human blood-brain barrier EC (BEC) express enzymatic activities capable of cleaving retained APP on activated platelets. Both control and AD-BEC express a and B-secretase-like proteases, with cells from Alzheimer's disease brains having an additional g-secretase-like activity. Additionally, we demonstrate the presence of platelet-derived Aa/APP fragments in the BEC layers of our model, supporting our hypothesis that platelets contribute to the cerebrovascular A\B and to the progression of Alzheimer's disease. We plan to pursue these findings by (1) studying the interactions between the endothelium and platelets by investigating the importance of our documented AD-specific APP processing defect in these interactions, utilizing a novel 4-layer model of the BBB, (2) investigating the passage of platelet-derived APP fragments and AB deposition in the underlying BEC and smooth muscle cell (SMC) layers of the cerebral vasculature and modulation of this transport by different isoforms of apo E, in particular apo E4 and (3) investigating the role of the serine and metallo-proteases present in BEC and SMC from autopsied brain of control and Alzheimer's disease patients, in facilitating the delivery of AB and APP fragments to the cerebrovasculature. Our goal is to determine the mechanism by which platelet-derived APP fragments or Aa are released, transferred through the sub endothelial layer of the cerebrovasculature and deposited between this layer and the SMC, in the hope of designing modalities to interfere with this process and slow the consequent progression of Alzheimer's disease.

描述：阿尔茨海默氏病（AD）患者的尸检表明 存在周围B淀粉样蛋白（AB）的有组织的沉积物 微脉管系统。 这些沉积物被认为起源于淀粉样蛋白 活化血小板释放的前体蛋白（APP）片段；这 这种沉积的机制在阿尔茨海默氏病的患者中发现但 不在控件中仍不清楚。 迄今为止，尚未显示是否应用程序 起源于血小板的碎片能够穿越 血脑屏障（BBB），然后导致神经AB沉积物。 我们已经证明了血小板中应用程序处理缺陷的存在 来自阿尔茨海默氏病的患者，导致APP保留 活化血小板的表面。 应用程序处理缺陷可能是 与大脑脉管系统中的AA斑块沉积有关。 我们有 开发了一个模型系统，利用血小板和内皮细胞（EC）， 并表明人类血脑屏障EC（BEC）表达酶促的 能够在激活血小板上切割保留应用程序的活动。 两个都 对照和AD-BEC表达A和B-分泌酶样蛋白酶，带有来自 阿尔茨海默氏病大脑具有额外的G-分泌酶样活性。 此外，我们演示了血小板衍生的AA/应用的存在 在我们模型的BEC层中的碎片，支持我们的假设 血小板有助于脑血管A \ B，并进展 阿尔茨海默氏病。 我们计划通过（1）研​​究 通过研究内皮和血小板之间的相互作用 我们已记录的特定AD应用程序处理缺陷的重要性 相互作用，利用BBB的新型4层模型，（2）研究 血小板衍生的应用片段和AB沉积的通过 大脑的基础BEC和平滑肌细胞（SMC）层 脉管系统和通过不同的同工型的Apo e进行调节， 特别是APO E4和（3）调查丝氨酸的作用和 BEC和SMC中存在的金属 - 蛋白酶，来自控制大脑的大脑和 阿尔茨海默氏病患者，促进AB和APP的交付 大脑碎片。 我们的目标是确定机制 通过哪些血小板衍生的应用片段或AA释放，转移 穿过大脑的子内皮层并沉积 在此层和SMC之间，希望将方式设计为 干扰这一过程并减缓随之而来的进展 阿尔茨海默氏病。