AMYLOID PRECURSOR PROTEIN IN NORMAL/DEMENTIA PLATELETS

正常/痴呆血小板中的淀粉样前体蛋白

• 批准号: 3123438
• 负责人: THERESA A DAVIES
• 金额: $ 23.82万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3123438
• 关键词: Alzheimer's disease; Downs syndrome; SDS polyacrylamide gel electrophoresis; amyloid proteins; biological signal transduction; clone cells; dementia; human subject; intracellular; neoplastic cell culture for noncancer research; nucleic acid sequence; platelets; protein biosynthesis; secretion; thrombin; western blottings

The characteristic deposits of beta-amyloid protein (beta-A4) in the brain and vasculature of Alzheimer's Disease (AD) patients were described many years ago. There is a strong indication that the beta-A4 originates from the amyloid precursor protein (beta-APP) which is present in many cells including megakaryocytes and the alpha-granules of platelets. Platelet activation by thrombin leads to secretion of granule contents, including beta-APP (known to inhibit Factor XIa), which participate in normal thrombosis and hemostasis. The mechanism of precursor release from platelets from AD, non-AD dementias and Downs Syndrome (DS) patients may differ from that of normal controls and has yet to be examined. Alternatively, the activation process and the beta-APP release may be normal in platelets from these patients but proteolysis of the precursor into the beta-A4 may be abnormal. It has already been shown that beta-APP is identical in non-familial AD and in normal individuals but differences in its secretion from platelets from AD and other dementias patients are only now being investigated. Furthermore, the proteolytic processing to form the amyloid peptide, and possibly the targeting of the peptide to specific tissues, may be different in dementias. Additionally, abnormalities in platelet function and morphology have been reported in AD, Parkinsons Disease (PSD) and DS which suggest further that disease-specific differences in the brain could be linked to platelet function. We hypothesize that beta-APP from platelets from patients with varying dementias may be characterizable by an abnormality in either the localization of, the form of, or the proteolytic products of beta-APP. Based on our extensive experience in the study of early platelet responses to agonists, including degranulation, we propose to investigate the quantity of, the form of, the release of, and the processing of beta-APP from AD, non-AD dementias, and DS platelets, in comparison to those individuals of comparable age. The proposed research aims are (1) to use a human megakaryocyte leukemic cell line (Dami) to examine the production, processing, and release characteristics of beta-APP from these cells; (2) to investigate differences in the size and quantity of the beta-amyloid precursor protein (beta-APP) released upon thrombin stimulation from platelets from patients with AD, DS, and other non-Alzheimer dementias and (3) to localize the beta-APP within the platelet by examining subcellular platelet fractions from patients with AD, DS, and other non-Alzheimer's dementias. We hope that our studies will help to delineate differences in the released beta-APP from AD, non-AD dementias and DS platelets and will lead to major insights into the role of platelet-contained beta-APP not only in dementias marked by amyloid deposits but also normal platelets, and hence in thrombosis and hemostasis.

β-淀粉样蛋白（β-A4）的特征沉积物在 描述了阿尔茨海默氏病（AD）患者的大脑和脉管系统 多年前。 有很大的迹象表明beta-A4起源于 来自许多存在于许多人中的淀粉样前体蛋白（β-App） 包括巨核细胞和血小板的α颗粒在内的细胞。 凝血酶的血小板激活导致颗粒含量分泌， 包括Beta-App（已知抑制因子Xia），参与 正常血栓形成和止血。 前体释放的机制 来自AD的血小板，非AD痴呆症和Downs综合征（DS）患者 可能与正常对照的不同，尚待检查。 另外，激活过程和β应用程序发布可能是 这些患者的血小板正常，但前体的蛋白水解 进入β-A4可能是异常的。 已经证明beta-app在非家庭广告中是相同的 在普通人中，但血小板的分泌差异 来自AD和其他痴呆症患者，直到现在才被研究。 此外，形成淀粉样肽的蛋白水解加工， 可能将肽靶向特定组织，可能是 痴呆症不同。 另外，血小板功能异常 帕金森氏病（PSD）和DS中已经报道了形态 这进一步暗示了大脑的疾病特异性差异 可以链接到血小板功能。 我们假设来自不同患者的血小板的Beta App 痴呆症的特征是通过异常 β-APP的定位，形式或蛋白水解产物。 根据我们在早期血小板研究方面的丰富经验 对激动剂的反应，包括脱粒，我们建议调查 的数量，形式，释放和处理的数量 相比之下 那些具有可比年龄的人。 拟议的研究目的是（1）使用人类的巨核细胞白血病 细胞系（DAMI）检查生产，加工和释放 来自这些细胞的β-APP的特征； （2）调查 β-淀粉样蛋白前体的大小和数量的差异 蛋白质（β-APP）在血小板刺激下释放的蛋白质（β-APP） 患有AD，DS和其他非Alz​​heimer痴呆症患者，（3）至 通过检查亚细胞将β-App定位在血小板中 AD，DS和其他非Alz​​heimer患者的血小板级分 痴呆症。 我们希望我们的研究将有助于描述差异 在AD，非AD痴呆症和DS血小板中发布的Beta-App中 将导致对含血小板的β-App的作用的重大见解 不仅以淀粉样蛋白沉积物为标志的痴呆症，而且正常 血小板，因此在血栓形成和止血中。