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.
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.
|Wang, Xiaochuan; Blanchard, Julie; Tung, Yunn Chyn et al. (2015) Inhibition of Protein Phosphatase-2A (PP2A) by I1PP2A Leads to Hyperphosphorylation of Tau, Neurodegeneration, and Cognitive Impairment in Rats. J Alzheimers Dis 45:423-35|
|Wang, Xiaochuan; Blanchard, Julie; Grundke-Iqbal, Inge et al. (2015) Memantine Attenuates Alzheimer's Disease-Like Pathology and Cognitive Impairment. PLoS One 10:e0145441|
|Iqbal, Khalid; Gong, Cheng-Xin; Liu, Fei (2014) Microtubule-associated protein tau as a therapeutic target in Alzheimer's disease. Expert Opin Ther Targets 18:307-18|
|Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin (2014) Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles. Biochem Pharmacol 88:631-9|
|Wang, Xiaochuan; Blanchard, Julie; Grundke-Iqbal, Inge et al. (2014) Alzheimer disease and amyotrophic lateral sclerosis: an etiopathogenic connection. Acta Neuropathol 127:243-56|
|Liu, Gong-Ping; Wei, Wei; Zhou, Xin et al. (2013) Silencing PP2A inhibitor by lenti-shRNA interference ameliorates neuropathologies and memory deficits in tg2576 mice. Mol Ther 21:2247-57|
|Wang, Jian-Zhi; Xia, Yi-Yuan; Grundke-Iqbal, Inge et al. (2013) Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimers Dis 33 Suppl 1:S123-39|