Involvement of 
in the abnormal hyperphosphorylation of tau and its reversal by Memantine
Abstract
The activity of protein phosphatase (PP)-2A, which regulates tau phosphorylation, is compromised in Alzheimer disease brain. Here we show that the transient transfection of PC12 cells with inhibitor-2 
of PP2A causes abnormal hyperphosphorylation of tau at Ser396/Ser404 and Ser262/Ser356. This hyperphosphorylation of tau is observed only when a sub-cellular shift of 
takes place from the nucleus to the cytoplasm and is accompanied by cleavage of 
into a 20
kDa fragment. Memantine, an un-competitive inhibitor of N-methyl-d-aspartate receptors, inhibits this abnormal phosphorylation of tau and cell death and prevents the 
inhibition of PP2A activity in vitro. These findings demonstrate novel mechanisms by which 
regulates the intracellular activity of PP2A and phosphorylation of tau, and by which Memantine modulates PP2A signaling and inhibits neurofibrillary degeneration.
Abbreviations: AD, Alzheimer disease, PP2A, protein phosphatase-2A, 
, inhibitor-2 of PP2A, NMDAR, N-methyl-d-aspartate receptor
Keywords: Alzheimer’s disease, Tau, Protein phosphatase-2A, Inhibitor-2 of PP2A, Memantine
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PII: S0014-5793(06)00724-1
doi:10.1016/j.febslet.2006.06.021
© 2006 Federation of European Biochemical Societies
