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(American Journal of Pathology. 2005;166:1761-1771.)
© 2005 American Society for Investigative Pathology

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

From the New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York

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 I₁^PP2A and I₂^PP2A, which regulate the intracellular activity of PP2A in mammalian tissues. We found a significant increase in the neocortical levels of I₁^PP2A and I₂^PP2A in AD as compared to control cases by in situ hybridization. The immunohistochemical studies revealed that I₂^PP2A was translocated from neuronal nuclei to cytoplasm in AD. The 39-kd full-length I₂^PP2A was selectively cleaved into an 20-kd fragment in AD brain cytosol. Digestion of the recombinant human I₂^PP2A 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 I₁^PP2A and I₂^PP2A in the abnormal hyperphosphorylation of tau in AD.

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