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 PC12 cells. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.