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 I1PP2A and I2PP2A. Previously, we reported that: (i) I1PP2A and I2PP2A are upregulated with cleavage of I2PP2A holoprotein and translocation of its amino terminal fragment from the nucleus to the cytoplasm in neuronal cells in AD brains; and (ii) translocated I2PP2A 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 I2PP2A is located between amino acids 175 and 176 of the I2PP2A sequence. Because the sequence from amino acids 168 to 181 on I2PP2A presumably functions as a nuclear localization signal (NLS), inhibition of break down of the NLS in I2PP2A is expected to be a novel therapeutic target for the treatment of Alzheimer's disease.