Phosphoprotein phosphatase 2A, a new target for Alzheimer's Disease interventio

描述(申请人提供)：tau的异常过度磷酸化在阿尔茨海默病(AD)和其他tau病中起着重要作用。目前针对tau激酶的治疗方法(如GSK-3、MAPK、CDK5、CK-1、PKA、CaMKII)受到多条多余的tau磷酸化途径的阻碍。相比之下，蛋白磷酸酶-2A(PP2A)是主要的tau磷酸酶，约占tau去磷酸化的70%，最近的研究表明其在AD中的表达和活性下调。PP2A的活性受可逆的羧甲基化控制，因此抑制去甲基化可能是恢复健康tau磷酸化水平的一种有前途的干预策略。围绕这一假设建立一个筛选平台，我们确定了一个小分子SIG1012，它以一种剂量依赖的方式降低N2a细胞中的p-tau水平，并对野生型小鼠口服有效地减少p-tau。初步药理数据表明，SIG1012具有非常有利的安全性和毒理学特征。拟议的第一阶段研究计划对于验证PP2A作为小分子有效干预AD的药物靶点至关重要。它概述了拟议的阿尔茨海默病动物模型有效性概念证明研究的具体步骤。关键的3xTg-AD小鼠和(AAV)-I2 CTF大鼠实验将与世界著名的tau在神经退行性疾病中的作用专家Khalid Iqbal博士合作进行。这项研究计划的成功完成将使SIG1012在第二阶段正式进入临床前开发阶段，成为治疗AD和其他肌萎缩侧索硬化症的“一流”PP2A调节剂。) 与公共卫生相关：阿尔茨海默病(AD)是一种进行性和致命性的脑部疾病，目前困扰着500多万美国人和全球2700多万人。目前AD的治疗方法在很大程度上并不令人满意，更有效的治疗方法的开发代表着巨大的未得到满足的医疗需求。这种新型磷酸蛋白调节剂的成功开发将为阿尔茨海默病患者提供一种重要的额外的、可能更好的治疗选择。

DESCRIPTION (provided by applicant): Abnormal hyperphosphorylation of tau plays an important role in Alzheimer's disease (AD) and other tauopathies. Current therapeutic approaches with focus on tau kinases (e.g. GSK-3, MAPK, cdk5, CK-1, PKA, CaMKII) are hindered by multiple and redundant tau phosphorylation pathways. In contrast, protein phosphatase-2A (PP2A) is the major tau phosphatase accounting for ~70% of tau dephosphorylation, and recent research shows that its expression and activity are down-regulated in AD. PP2A activity is governed by reversible carboxyl-methylation, thus inhibiting demethylation might be a promising intervention strategy to restore healthy tau phosphorylation levels. Building a screening platform around this hypothesis, we identified a small molecule SIG1012, which reduces p-tau levels in N2a cells in a dose-dependent manner and is orally efficacious in reducing p-tau in wild type mice. Preliminary pharmacological data suggests that SIG1012 has highly favorable safety and toxicology profiles. The proposed Phase I research plan is critical to validating PP2A as a pharmaceutical target for effective intervention in AD by a small molecule. It outlines specific steps for the proposed proof of concept studies of efficacy in animal models of AD. The critical 3xTg-AD mouse and (AAV)-I2 CTF rat experiments will be carried out in collaboration with Dr. Khalid Iqbal, a world- renowned expert on the role of tau in neurodegenerative diseases. Successful completion of this research proposal will lead in Phase II to formal preclinical development of SIG1012 as the "first-in-class" PP2A modulating agent for treatment of AD and other tauopathies. ) PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a progressive and fatal brain disease that afflicts over 5 million Americans today and over 27 million people worldwide. Current treatments of AD are largely unsatisfactory and development of more effective therapies represents a great unmet medical need. Successful development of this novel class of phosphoprotein modulators will provide an important additional, and potentially better, therapeutic option for people suffering from AD.