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

AbstractProtein phosphatase (PP)-2A, which regulates the phosphorylation of tau, is regulated by two endogenous inhibitor proteins, I1PP2A and I2PP2A, in mammalian tissues. Here, we report the cloning of I1PP2A and I2PP2A from human brain, and show that in PC12 cells and in I1PP2A-GFP or I2PP2A-GFP transfected NIH3T3 and human neural progenitor cells, I1PP2A is localized mostly in the cell cytoplasm and I2PP2A mostly in the nucleus. The recombinant I1PP-2A and I2PP-2A inhibit PP-2A activity towards hyperphosphorylated tau in vitro; the dephosphorylation of the hyperphosphorylated tau at specific sites is selectively inhibited. Overexpression of I1PP2A as well as I2PP2A results in tau hyperphosphorylation and degeneration of PC 12 cells