SELECTIVE PHOSPHORYLATION OF ADULT TAU-ISOFORMS IN MATURE HIPPOCAMPAL-NEURONS EXPOSED TO FIBRILLAR A-BETA

How senile plaques and neurofibrilliary tangles are linked represents a major gap in our understanding of the pathophysiology of Alzheimer's disease. We characterized a hippocampal neuronal culture system in wh ich tau undergoes maturation in vivo; rat neurons maintained in cultur e for more than 3 weeks replicated the splicing and phosphorylation ch anges that tau undergoes upon maturation in situ. Using this model sys tem, we induced an Alzheimer-like neuritic dystrophy following the app lication of fibrillar beta-amyloid. The dystrophy consisted of focal d istortions and swellings within the neurites and an altered phosphoryl ation of the adult tau isoforms, Fibrillar beta-amyloid induced the co ncomitant activation of MAP kinase and GSK3 beta. The aberrant activat ion of several signaling pathways may lead to the abnormal phosphoryla tion of tau and neuritic degeneration.