IGF-1 promotes β-amyloid production by a secretase-independent mechanism

beta-Amyloid peptide (A) is generated via the sequential proteolysis of beta-amyloid precursor protein (APP) by beta- and gamma-secretases, and plays a Crucial role in the pathogenesis of Alzheimer's disease (AD). Here, we sought to clarify the role of insulin-like growth factor-1 (IGF-1), implicated in the AD pathomechanism, in the generation of AV. Treatment of neuroblastoma SH-SY5Y cells expressing AD-associated Swedish mutant APP with IGF-1 did not alter cellular levels of APP, but significantly increased those of P-C-terminal fragment (beta-CTF) and secreted A beta, IGF-1 also enhanced APP phosphorylation at Thr668. Treatment of beta-CTF-expressing cells with IGF-1 increased the levels of beta-CTF and secreted A beta. The IGF-1-induced augmentation of beta-CTF was observed in the presence of gamma-secretase inhibitors, but not in cells expressing beta-CTF with a Thr668 to alanine substitution. These results suggest that IGF-1 promotes A beta production through a secretase-independent mechanism involving APP phosphorylation. (C) 2009 Elsevier Inc. All rights reserved.