I2PP2A: A Therapeutic Target

描述（由申请人提供）：阿尔茨海默病（AD）是老年人痴呆症最常见的病因，在美国占500多万例，在中国占600万例，在全球占2000多万例。大脑中微管相关蛋白tau的异常过度磷酸化和b-淀粉样蛋白（Ab）的形成是AD的两个标志性病理过程。虽然tau过度磷酸化和Ab过度产生的机制已经被广泛研究，但目前还没有有效的治疗方法。迄今为止，旨在单独消除Ab的治疗性临床试验一直令人失望。因此，同时抑制tau异常过度磷酸化和Ab过量产生的新靶点值得研究。基于我们之前的研究表明，AD大脑中脑蛋白磷酸酶2A （PP2A）选择性降低，以及该酶的内源性蛋白抑制剂I1PP2A和I2PP2A参与AD的发病机制，我们的长期目标是基于这一疾病机制开发一种有效的治疗AD神经退行性变的方法。这项为期三年的Fogarty国际研究合作奖（FIRCA）的具体目标是研究敲低抑制剂-2 （I2PP2A）是否是一个有价值的靶标，以抑制tau/Ab病理，并在明确定义的三重转基因AD小鼠模型（3xTgAD）中拯救记忆缺陷。为此，我们提出以下两个具体目的：(1)研究I2PP2A敲除是否能抑制3xTgAD小鼠tau/神经原纤维变性和b-淀粉样变性异常高磷酸化；(2)研究敲低I2PP2A是否能抑制这些动物的神经变性及相关的认知功能障碍。这些研究将有助于验证AD药物开发的合理治疗靶点，并将促进申请人在美国的实验室与外国合作者在中国的实验室之间的国际研究合作。本研究将主要在中国武汉的华中科技大学进行，与王建志合作，作为NIH拨款号的延伸。R01 AG019158, 2007年5月1日至2012年4月30日。本次FIRCA申请的目的是延伸和扩展美国实验室和外国合作者实验室的研究项目，这将有助于阐明抑制I2PP2A是否可以恢复PP2A活性并挽救AD型组织病理学和认知，从而为AD药物开发提供有效的治疗靶点。验证基于疾病的合理治疗靶点，从而开发一种或多种有效的治疗AD及相关疾病的药物，对美国和中国都具有高度相关性和高度优先性。

DESCRIPTION (provided by applicant): Alzheimer disease (AD) is the most common cause of dementia in the elderly, which accounts for over five million cases in the United States, six million in the P.R. China, and over 20 million cases worldwide. Abnormal hyperphosphorylation of the microtubule associated protein tau and formation of b-amyloid (Ab) in the brain are the two hallmark pathological processes in AD. Although the mechanisms underlying tau hyperphosphorylation and Ab overproduction have been extensively studied, there is currently no effective cure for this disease. The therapeutic clinical trials aimed at eliminating Ab alone have been disappointing, to date. Therefore, new target(s) to inhibit simultaneously abnormal hyperphosphorylation of tau and Ab overproduction warrant investigation. Based on our previous studies which showed a selective decrease in brain protein phosphatase 2A (PP2A) in AD brain and the involvement of the endogenous protein inhibitors, I1PP2A and I2PP2A, of this enzyme in the etiopathogenesis of AD, our long-term objective is to develop an effective treatment for AD neurodegeneration based on this disease mechanism. The specific objective of this three-year Fogarty International Research Collaboration Award (FIRCA) is to study whether knockdown of inhibitor-2 (I2PP2A) is a valuable target to inhibit tau/Ab pathologies and to rescue the memory deficit in a well-defined triple transgenic mouse model of AD (3xTgAD). Towards this goal, we propose the following two specific aims: (1) To study whether knockdown of I2PP2A can inhibit abnormal hyperphosphorylation of tau/neurofibrillary degeneration and b-amyloidosis in 3xTgAD mice; and (2) To study whether knockdown of I2PP2A can inhibit neurodegeneration and associated cognitive impairment in these animals. These studies will help validate a rational therapeutic target for drug development of AD, and will also foster international research collaboration between the applicant's laboratory in the United States and the Foreign Collaborator's laboratory in China. This research will be done primarily in Huazhong University of Science and Technology, Wuhan, P.R. China, in collaboration with Jian-Zhi Wang, as an extension of NIH Grant No. R01 AG019158, 5/1/2007 to 4/30/2012. The objective of this FIRCA application is to extend and expand the research programs of both the United States laboratory and the Foreign Collaborator's laboratory that will help elucidate whether inhibition of I2PP2A can restore PP2A activity and rescue AD-type histopathology and cognition, and thus to provide an effective therapeutic target for AD drug development. Validation of a disease-based rational therapeutic target that can lead to the development of one or more effective therapeutic drugs for AD and related disorders is highly relevant and a high priority both for the United States and for the P.R. China. PUBLIC HEALTH RELEVANCE: Alzheimer disease (AD) and related disorders, characterized by neurofibrillary degeneration of abnormally hyperphosphorylated tau, are the major causes of middle- to old-age dementia, and constitute a major public health problem in the United States, in the P.R. China, and worldwide. The objective of this FIRCA grant application is to enhance, extend, and expand international research collaboration on this global health problem by jointly investigating the validity of I2PP2A, an inhibitor protein phosphatase (PP) -2A that regulates the phosphorylation of tau, as a therapeutic target. The abnormally hyperphosphorylated tau protein is the major protein subunit of neurofibrillary tangles, a hallmark histopathological brain lesion of individuals with AD, adults with Down syndrome, and individuals with related tauopathies.