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

 描述（由申请人提供）：我们对遗传和环境因素以及它们产生阿尔茨海默病特征性认知和行为障碍的机制的理解不足，是确定阿尔茨海默病有效预防措施和治疗的关键障碍。该项目旨在通过检查丝氨酸/苏氨酸蛋白磷酸酶PP 2A控制对β-淀粉样蛋白病理作用的敏感性的能力来解决我们理解中的这一差距，β-淀粉样蛋白是一种在阿尔茨海默病患者大脑中积累的蛋白质。PP 2A受多种机制调节，包括催化亚基C-末端的翻译后甲基化。这种甲基化由专用的甲基酯酶PME-1和专用的甲基转移酶LCMT-1控制。为了进行这些研究，我们将使用多个系的遗传修饰小鼠通过操纵PME-1和LCMT-1表达来改变PP 2A的体内活性。通过改变PP 2A甲基化，成熟酶的亚基组成和底物特异性将被改变，从而增加或降低其使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）检验PP 2A甲基化降低通过增加对β-淀粉样蛋白的敏感性促进阿尔茨海默病相关损伤的发展的假设。2)检验过表达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保护免受阿尔茨海默病相关损伤的假设。3)检验PP 2A通过调节APP在Thr 668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，电生理和生物化学技术的组合来解决。总之，来自这些研究的发现将确定PP 2A及其下游靶点可能通过控制对β-淀粉样蛋白的敏感性来影响阿尔茨海默病发展的机制。此外，他们将建议开发针对该途径的干预措施，作为该疾病的有效新治疗方法。

 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.