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Inhibition of Protein Phosphatase-2A (PP2A) by I1PP2A Leads to Hyperphosphorylation of Tau, Neurodegeneration, and Cognitive Impairment in Rats.

Journal of Alzheimer's disease : JAD (2015-01-16)
Xiaochuan Wang, Julie Blanchard, Yunn Chyn Tung, Inge Grundke-Iqbal, Khalid Iqbal
ABSTRACT

Protein phosphatase-2A (PP2A) deficiency is a cause of the abnormal hyperphosphorylation of tau, which composes neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. We previously reported that both mRNA and protein expression of inhibitor I of PP2A (I(1)(PP2A)) are elevated in AD brain and that this inhibitor induces a dose-dependent inhibition of PP2A activity and tau hyperphosphorylation in NIH3T3 cells. However, whether I(1)(PP2A) can induce AD neurofibrillary degeneration and cognitive impairment was not known. In the present study, we infected the brains of rat pups within 24 hours of birth with adeno-associated virus serotype 1 (AAV1) carrying I(1)(PP2A). In the adult AAV1-I(1)(PP2A) rats, we found a decrease in PP2A activity and abnormal hyperphosphorylation of tau in the brain. Immunohistochemistry showed a significant reduction of MAP2 and synapsin 1 in AAV1- I(1)(PP2A) animals, suggesting that I(1)(PP2A) can induce a loss of dendritic and synaptic plasticity markers. Behavioral tests revealed that infection with AAV1- I(1)(PP2A) induced deficits in exploratory activity, spatial reference memory, and memory consolidation in adult rats. These studies suggest that I(1)(PP2A) can inhibit PP2A activity, and in turn induce AD neurofibrillary degeneration and cognitive deficits in rats.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
邻二甲苯, anhydrous, 97%
Sigma-Aldrich
邻二甲苯, puriss. p.a., ≥99.0% (GC)
Sigma-Aldrich
邻二甲苯, reagent grade, ≥98.0%
Supelco
邻二甲苯, analytical standard
Supelco
邻二甲苯, suitable for HPLC, 98%
Supelco
邻二甲苯, Pharmaceutical Secondary Standard; Certified Reference Material
碘克沙醇, European Pharmacopoeia (EP) Reference Standard