Inhibitors of protein phosphatase‐2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau

Protein phosphatase (PP)‐2A, which regulates the phosphorylation of tau, is regulated by two endogenous inhibitor proteins,I 1 PP 2 AandI 2 PP 2 A, in mammalian tissues. Here, we report the cloning ofI 1 PP 2 AandI 2 PP 2 Afrom human brain, and show that in PC12 cells and inI 1 PP 2 A ‐ GFP orI 2 PP 2 A ‐ GFP transfected NIH3T3 and human neural progenitor cells,I 1 PP 2 Ais localized mostly in the cell cytoplasm andI 2 PP 2 Amostly in the nucleus. The recombinantI 1 PP ‐ 2 AandI 2 PP ‐ 2 Ainhibit PP‐2A activity towards hyperphosphorylated tau in vitro; the dephosphorylation of the hyperphosphorylated tau at specific sites is selectively inhibited. Overexpression ofI 1 PP 2 Aas well asI 2 PP 2 Aresults in tau hyperphosphorylation and degeneration of PC 12 cells.