Demonstration by fluorescence resonance energy transfer of a close association between activated MAP kinase and neurofibrillary tangles: Implicationsfor MAP kinase activation in Alzheimer disease

Indirect evidence suggests that activation of the mitogen activated protein kinase (MAPK) cascade contributes to the hyperphosphorylation of tau found in paired helical filaments in Alzheimer disease (AD). We report colocaliz ation of the activated form of MAPK with Ser 199/202 and Ser 396/404 phosph otau immunoreactive neurofibrillary tangles and neuritic plaques in the Alz heimer brain. Fluorescence resonance energy transfer studies (FRET) demonst rate a tight intermolecular association of activated MAPK with these phosph otau epitopes. These data support the hypothesis that activation of MAPK co ntributes directly to phosphorylation of tau in AD. Moreover, the stable na ture of this association in postmortem human brain may suggest a stable int eraction in which activated MAPK becomes tightly linked to neurofibrillary tangles.