EFFECT OF GLYCOGEN SYNTHASE KINASE 3 β-MEDIATED PRESENILIN 1 PHOSPHORYLATION ON AMYLOID β PRODUCTION IS NEGATIVELY REGULATED BY INSULIN RECEPTOR CLEAVAGE

Presenilin 1 (PS1), a causative molecule of familial Alzheimer's disease (AD), is known to be an unprimed substrate of glycogen synthase kinase 3 beta (GSK3 beta) [Twomey and McCarthy (2006) FEBS Lett 580:4015-4020] and is phosphorylated at serine 353, 357 residues in its cytoplasmic loop region [Kirschenbaum et al. (2001) J Biol Chem 276:7366 7375]. In this report, we investigated the effect of PSI phosphorylation on AD pathophysiology and obtained two important results PSI phosphorylation increased amyloid beta (A beta) 42140 ratio, and PSI phosphorylation was enhanced in the human AD brains. Interestingly, we demonstrated that PS1 phosphorylation promoted insulin receptor (IR) cleavage and the IR intracellular domain (IR ICD) generated by gamma-secretase led to a marked transactivation of Akt (PKB), which down-regulated GSK3 beta activity. Thus, the cleavage of IR by gamma-secretase can inhibit PSI phosphorylation in the long run. Taken together, our findings indicate that PSI phosphorylation at serine 353, 357 residues can play a pivotal role in the pathology of AD and that the dysregulation of this mechanism may be causally associated with its pathology. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.