Up-Regulation of Inhibitors of Protein Phosphatase-2A in Alzheimer's Disease

The activity of protein phosphatase-2A (PP2A) 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 I1PP2A and I2PP2A, which regulate the intracellular activity of PP2A in mammalian tissues. We found a significant increase in the neocortical levels of I1PP2A and I2PP2A in AD as compared to control cases by in situ hybridization. The immunohistochemical studies revealed that I2PP2A was translocated from neuronal nuclei to cytoplasm in AD. The 39-kd full-length I2PP2A was selectively cleaved into an ∼20-kd fragment in AD brain cytosol. Digestion of the recombinant human I2PP2A with AD brain extract showed an increase in the generation of the ∼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 I1PP2A and I2PP2A in the abnormal hyperphosphorylation of tau in AD.