IGF-1 promotes beta-amyloid production by a secretase-independent mechanism.
Beta-amyloid peptide (Abeta) 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 Abeta. 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 beta-C-terminal fragment (beta-CTF) and secreted Abeta. 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 Abeta. 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 Abeta production through a secretase-independent mechanism involving APP phosphorylation.
Araki
Wataru
W
Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. araki@ncnp.go.jp
Kume
Hideaki
H
Oda
Akiko
A
Tamaoka
Akira
A
Kametani
Fuyuki
F
D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary
D016564:Amyloid beta-Protein Precursor; D007334:Insulin-Like Growth Factor I; D053829:Amyloid Precursor Protein Secretases