Demonstration by fluorescence resonance energy transfer of a close association between activated MAP kinase and neurofibrillary tangles: implications for 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 colocalization of the activated form of MAPK with Ser 199/202 and Ser 396/404 phosphotau immunoreactive neurofibrillary tangles and neuritic plaques in the Alzheimer brain. Fluorescence resonance energy transfer studies (FRET) demonstrate a tight intermolecular association of activated MAPK with these phosphotau epitopes. These data support the hypothesis that activation of MAPK contributes directly to phosphorylation of tau in AD. Moreover, the stable nature of this association in postmortem human brain may suggest a stable interaction in which activated MAPK becomes tightly linked to neurofibrillary tangles.