Inhibition of protein phosphatase 2A induces phosphorylation and accumulation of neurofilaments in metabolically active rat brain slices.

In Alzheimer disease (AD) brain neurofilaments (NF) in addition to tau are hyperphosphorylated and accumulated and the activity of the phosphoprotein phosphatase 2A (PP2A) is compromised. In this study, employing metabolically competent brain slices from adult rats, we investigated whether such a NF abnormality could be caused by the down-regulation of PP2A activity. After 3 h treatment with 1.0 microM okadaic acid, the PP2A activity was inhibited by approximately 70% in the brain slices. We found that the inhibition of PP2A induced an increase in the phosphorylation of NF-H and NF-M subunits and in the level of NF-H. Immunohistochemical examination revealed that the PP2A inhibition resulted in increased phosphorylation of NF in the axon and a general accumulation of NF throughout the whole neuron. These findings suggest that the hyperphosphorylation and accumulation of NF found in AD brain could have been caused by the down-regulation of PP2A. Copyright 2003 Elsevier Science Ireland Ltd.