Effect of GSK3-mediatedPS1 phosphorylation on A production is negatively regulated by IR cleavage

Presenilin 1 (PS1), a causative molecule of familial Alzheimer's disease (AD), is known to be an unprimed substrate of GSK3 (Twomey et al. 2006) and is phosphorylated at serine 353, 357 residues in its cytoplasmic loop region (Kirschenbaum et al. 2001). In this report, we investigated the effect of PS1 phosphorylation on AD pathophysiology and obtained two important results – PS1 phosphorylation increased A42/40 ratio, and PS1 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 γ-secretase led to a marked transactivation of Akt (PKB), which down-regulated GSK3activity. Thus, the cleavage of IR by γ-secretase can inhibit PS1 phosphorylation in the long run. Taken together, our findings indicate that PS1 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.