Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain - Implications for neurofibrillary degeneration in Alzheimer's disease

Hyperphosphorylated tau, which is the major protein of the neurofibrillary tangles in Alzheimer's disease brain, is most probably the result of an imb alance of tau kinase and phosphatase activities in the affected neurons. By using metabolically competent rat brain slices as a model, we found that s elective inhibition of protein phosphatase 2A by okadaic acid induced an Al zheimer-like hyperphosphorylation and accumulation of tau, The hyperphospho rylated tau had a reduced ability to bind to microtubules and to promote mi crotubule assembly in vitro. Immunocytochemical staining revealed hyperphos phorylated tau accumulation in pyramidal neurons in cornu ammonis and in ne ocortical neurons, The topography of these changes recalls the distribution of neurofibrillary tangles in Alzheimer's disease brain. Selective inhibit ion of protein phosphatase 2B with cyclosporin A did not have any significa nt effect on tan phosphorylation, accumulation, or function. These studies suggest that protein phosphatase 2A participates in regulation of tau phosp horylation, processing, and function in vivo. A down-regulation of protein phosphatase 2A activity can lead to Alzheimer-like abnormal hyperphosphoryl ation of tau.