tPA/Plasminogen System in Alzheimer's Disease Pathology

tPA/纤溶酶原系统在阿尔茨海默病病理学中的作用

• 批准号: 6487920
• 负责人: JERRY P MELCHOR
• 金额: $ 3.66万
• 依托单位: ROCKEFELLER UNIVERSITY
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6487920
• 关键词: Alzheimer's disease; amyloid proteins; behavior test; brain disorder chemotherapy; cognition; disease /disorder model; gene mutation; genetically modified animals; histochemistry /cytochemistry; injection /infusion; laboratory mouse; molecular pathology; neurons; neuropathology; neuroprotectants; neurotoxins; nonhuman therapy evaluation; plasmin; plasminogen; plasminogen activator; polymerase chain reaction; protein structure function; proteolysis

Alzheimer's disease (AD) is the leading cause of dementia in aged individuals. Of the pathologic hallmarks of AD is the formation of senile plaques, mostly composed of aggregated beta-amyloid (Abeta) peptide. Studies in vitro and in cell culture implicate the tissue plasminogen activator/plasminogen (tPA/pig) system in AD. (Aggregated Abeta peptide stimulates the activity of the tPA enzyme. The addition of aggregated Abeta peptide also leads to the elevation of tPA mRNA and plasmin, formed from plasminogen by tPA, can cleave the Abeta peptide attenuating the neurotoxicity.) The tPA system contributes to excitotoxic neuronal degeneration, a type of cell death observed in AD. This proposal will to address the effect of the tPA/pig system in the deposition of the Abeta peptide and the progression of AD. First, the clearance of Abeta will be investigated in mice deficient in molecules of the tPA/pig system (i.e. tPA-/- pig-/-). Additionally, by crossing mouse models engineered to exhibit AD pathology (Abeta plaques and cognitive deficit) with tPA-/- or pig-/- mice, we hope to define the effect of the tPA system n AD pathogenesis. The final part of this study will focus on the therapeutic possibilities that arise from the effect of the tPA/pig system in the progression of Alzheimer's disease.

阿尔茨海默病（AD）是老年人痴呆的主要原因。 AD 的病理特征是老年斑的形成，主要由聚集的 β-淀粉样 (Abeta) 肽组成。体外和细胞培养研究表明组织纤溶酶原激活剂/纤溶酶原 (tPA/猪) 系统与 AD 有关。 （聚集的 Abeta 肽会刺激 tPA 酶的活性。添加聚集的 Abeta 肽还会导致 tP​​A mRNA 升高，并且 tPA 由纤溶酶原形成的纤溶酶可以裂解 Abeta 肽，从而减弱神经毒性。）tPA 系统有助于兴奋性毒性神经元变性，AD 中观察到的一种细胞死亡类型。 该提案将解决 tPA/猪系统对 Abeta 肽沉积和 AD 进展的影响。首先，将在缺乏 tPA/猪系统分子（即 tPA-/- pig-/-）的小鼠中研究 Abeta 的清除情况。此外，通过将表现出 AD 病理学（Abeta 斑块和认知缺陷）的小鼠模型与 tPA-/- 或猪-/- 小鼠进行交叉，我们希望确定 tPA 系统在 AD 发病机制中的作用。本研究的最后部分将重点关注 tPA/猪系统在阿尔茨海默病进展中的作用所产生的治疗可能性。