Novel therapeutic strategies for neurodegenerative disease.

The activity of protein phosphatase 2A (PP2A) is compromised and believed to be the cause of the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain. Activity of PP2A is regulated by two endogeneous inhibitor proteins, called as I(1)(PP2A) and I(2)(PP2A). Previously, we reported that: (i) I(1)(PP2A) and I(2)(PP2A) are upregulated with cleavage of I(2)(PP2A) holoprotein and translocation of its amino terminal fragment from the nucleus to the cytoplasm in neuronal cells in AD brains; and (ii) translocated I(2)(PP2A) colocalized not only with the PP2A catalytic subunit, but also with phosphorylated tau in neuronal cytoplasm. Furthermore, according to preliminary data, the cleavage site of I(2)(PP2A) is located between amino acids 175 and 176 of the I(2)(PP2A) sequence. Because the sequence from amino acids 168 to 181 on I(2)(PP2A) presumably functions as a nuclear localization signal (NLS), inhibition of break down of the NLS in I(2)(PP2A) is expected to be a novel therapeutic target for the treatment of Alzheimer's disease.