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

描述（由申请人提供）：tau异常高磷酸化在阿尔茨海默病（AD）和其他tau病中起重要作用。目前以tau激酶（如GSK-3、MAPK、cdk5、CK-1、PKA、CaMKII）为重点的治疗方法受到多个冗余tau磷酸化途径的阻碍。相反，蛋白磷酸酶2a （protein phosphatase- 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活性受可逆羧基甲基化控制，因此抑制去甲基化可能是恢复健康的tau磷酸化水平的一种有希望的干预策略。围绕这一假设建立筛选平台，我们发现了一个小分子SIG1012，它以剂量依赖的方式降低N2a细胞中的p-tau水平，并且在野生型小鼠中口服有效降低p-tau。初步药理数据表明，SIG1012具有良好的安全性和毒理学特征。拟议的I期研究计划对于验证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AD动物模型有效性概念验证研究的具体步骤。关键的3xTg-AD小鼠和(AAV)- i2 CTF大鼠实验将与世界知名的tau在神经退行性疾病中的作用专家Khalid Iqbal博士合作进行。该研究计划的成功完成将导致SIG1012在II期正式临床前开发，作为治疗AD和其他tau病的“一流”PP2A调节剂。

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.