The regulation of beta-amyloid sensitivity and Alzheimer's related impairments by PP2A

 描述(由申请人提供)：我们对阿尔茨海默病的遗传和环境因素以及它们产生认知和行为障碍的机制缺乏了解，这是确定有效的阿尔茨海默病预防措施和治疗的关键障碍。这个项目试图通过检测丝氨酸/苏氨酸蛋白磷酸酶(PP2A)控制β-淀粉样蛋白病理行为的敏感性的能力来解决我们理解中的这一差距。β-淀粉样蛋白是一种积聚在阿尔茨海默病患者大脑中的蛋白质。PP2A受多种机制调控，包括催化亚基C末端的翻译后甲基化。这种甲基化是由专用甲基酯酶PME-1和专用甲基转移酶LCMT-1控制的。为了进行这些研究，我们将通过使用多个转基因小鼠品系来操纵PME-1和LCMT-1的表达，从而在体内改变PP2A的活性。通过改变PP2A甲基化，成熟酶的亚基组成和底物专一性将会改变，从而增加或降低其对阿尔茨海默病相关底物去磷酸化的能力。将追求以下具体目标：1)测试PP2A甲基化减少通过增加对β-淀粉样蛋白的敏感性而促进阿尔茨海默病相关损害的发展的假设。2)测试过表达LCMT-1或减少PME-1表达通过降低对β-淀粉样蛋白的敏感性来预防阿尔茨海默病相关损伤的假设。3)验证PP2A通过调节Thr668处APP的磷酸化来控制β-淀粉样蛋白敏感性的假设。这些目标将通过行为、电生理和生化技术的组合来实现。总而言之，这些研究的结果将确定PP2A及其下游靶点可能通过控制对β-淀粉样蛋白的敏感性而影响阿尔茨海默病发展的机制。此外，他们将建议开发针对这一途径的干预措施，作为治疗该疾病的有效新方法。

 DESCRIPTION (provided by applicant): Our poor understanding of the genetic and environmental factors and the mechanisms by which they produce the cognitive and behavioral impairments that characterize Alzheimer's disease stands as a critical barrier to identifying effective preventative measures and treatments for Alzheimer's disease. This project seeks to address this gap in our understanding by examining the ability of the serine/threonine protein phosphatase, PP2A, to control sensitivity to the pathological actions of beta-amyloid, a protein that accumulates in the brain of Alzheimer's disease patients. PP2A is regulated by multiple mechanisms including post-translational methylation of the C-terminus of the catalytic subunit. This methylation is controlled by a dedicated methylesterase, PME-1, and a dedicated methyltransferase, LCMT-1. To perform these studies, we will alter PP2A activity in vivo by manipulating PME-1 and LCMT-1 expression using multiple lines of genetically modified mice. By altering PP2A methylation, the subunit composition and substrate specificity of the mature enzyme will be altered, thereby increasing or decreasing its ability to dephosphorylate Alzheimer's disease relevant substrates. The following specific aims will be pursued: 1) Test the hypothesis that reduced PP2A methylation promotes the development of Alzheimer's disease related impairments by increasing sensitivity to beta- amyloid. 2) Test the hypothesis that over expressing LCMT-1 or reducing PME-1 expression protects against Alzheimer's disease related impairments by decreasing sensitivity to beta- amyloid. 3) Test the hypothesis that PP2A controls beta-amyloid sensitivity by regulating APP phosphorylation at Thr668. These aims will be addressed through a combination of behavioral, electrophysiological, and biochemical techniques. In summary, findings derived from these studies will identify the mechanisms whereby PP2A and its downstream targets may affect the development of Alzheimer's disease by controlling sensitivity to beta-amyloid. Furthermore, they will suggest developing interventions that target this pathway as an effective new therapeutic approach for the disease.