PRESENILIN-1 ASSOCIATES WITH GLYCOGEN-SYNTHASE KINASE-3-BETA AND ITS SUBSTRATE TAU

Families bearing mutations in the presenilin 1 (PS1) gene develop Alzh eimer's disease. Previous studies have shown that the Alzheimer-associ ated mutations in PS1 increase production of amyloid beta protein (A b eta(1-42)) We now show that PS1 also regulates phosphorylation of the microtubule-associated protein tau. PS1 directly binds tau and a tau k inase, glycogen synthase kinase 3 beta (GSK-3 beta), Deletion studies show that both tau and GSK-3 beta bind to the same region of PS1, resi dues 250-298, whereas the binding domain on tau is the microtubule-bin ding repeat region. The ability of PSI to bring tau and GSK-3 beta int o close proximity suggests that PSI may regulate the interaction of ta u with GSK-3 beta. Mutations in PS1 that cause Alzheimer's disease inc rease the ability of PS1 to bind GSK-3 beta and, correspondingly, incr ease its tau-directed kinase activity. We propose that the increased a ssociation of GSK-3 beta with mutant PSI leads to increased phosphoryl ation of tau.