Compartmentalized tau hyperphosphorylation and increased levels of kinasesin transgenic mice

The formation of neurofibrillary tangles in Alzheimer's disease is preceded by a pretangle stage of hyperphosphorylated tau. To characterize pretangle tau in vivo, we correlated, in human tau transgenic mice, levels of kinase s known to phosphorylate tau in vitro with the phosphorylation of tau at sp ecific epitopes. Levels of cyclin-dependent kinase-5 were increased in axon s of CAI pyramidal neurons, where tau was phosphorylated specifically at th e AD2 epitope Ser396/Ser404. The 12E8 epitope serine262/serine356 and the A T180 epitope threonine231/serine235 were phosphorylated in dendrites, and c olocalized with increased levels of glycogen synthase kinase-3. CAI neurons phosphorylated tau at more epitopes than dentate gyrus neurons, suggesting that tau phosphorylation is cell type-specific, a possible explanation for the spatial distribution of neurofibrillary tangles. NeuroReport 12:2007-2 016 (C) 2001 Lippincott Williams & Wilkins.