Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer's disease

The activity of protein phosphatase-2A (MA) is compromised and is believed to be a cause of the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain. We investigated in AD the role of the two known endogenous PP2A inhibitors, called I-2(PP2A) and 12, which regulate the intracellular activity of PP2A in mammalian tissues. We found a significant increase in the neocortical levels of I-2(PP2A) and I-2(PP2A) in AD as compared to control cases by in situ hybridization. The immunohistochemical studies revealed that I-2(PP2A) was translocated from neuronal nuclei to cytoplasm in AD. The 39-kd full-length I-2(PP2A) was selectively cleaved into an similar to 20-kd fragment in AD brain cytosol. Digestion of the recombinant human I-2(PP2A) with AD brain extract showed an increase in the generation of the similar to 20 kd and other fragments of the inhibitor as compared to control brain extract. Double-immunohistochemical studies revealed co-localization of PP2A with PP2A inhibitors in neuronal cytoplasm and co-localization of the inhibitors with abnormally hyperphosphorylated tau. These studies suggest the possible involvement of I-1(PP2A) and I-2(PP2A) in the abnormal hyperphosphorylation of tau in AD.