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)(PP2A) and I(2)(PP2A), in mammalian tissues. Here, we report the cloning of I(1)(PP2A) and I(2)(PP2A) from human brain, and show that in PC12 cells and in I(1)(PP2A)-GFP or I(2)(PP2A)-GFP transfected NIH3T3 and human neural progenitor cells, I(1)(PP2A) is localized mostly in the cell cytoplasm and I(2)(PP2A) mostly in the nucleus. The recombinant I(1)(PP-2A) and I(2)(PP-2A) inhibit PP-2A activity towards hyperphosphorylated tau in vitro; the dephosphorylation of the hyperphosphorylated tau at specific sites is selectively inhibited. Overexpression of I(1)(PP2A) as well as I(2)(PP2A) results in tau hyperphosphorylation and degeneration of PC 12 cells.