Title | Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Son, SMin, Shin, H-J, Byun, J, Kook, SYoung, Moon, M, Chang, YJin, Mook-Jung, I |
Journal | J Alzheimers Dis |
Volume | 51 |
Issue | 4 |
Pagination | 1197-208 |
Date Published | 2016 |
ISSN | 1875-8908 |
Keywords | Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases, Animals, Autophagy, Cell Line, Tumor, Disease Models, Animal, Female, Humans, Hypoglycemic Agents, Lysosomes, Metformin, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Mutation, Neuroblastoma, Signal Transduction |
Abstract | The evidence of strong pathological associations between type 2 diabetes and Alzheimer's disease (AD) has increased in recent years. Contrary to suggestions that anti-diabetes drugs may have potential for treating AD, we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage®) increased the generation of amyloid-β (Aβ), one of the major pathological hallmarks of AD, by promoting β- and γ-secretase-mediated cleavage of amyloid-β protein precursor (AβPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome accumulation in Tg6799 AD model mice. Extremely high γ-secretase activity was also detected in autophagic vacuoles, apparently a novel site of Aβ peptide generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased γ-secretase activity and Aβ generation. Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing in autophagosomes. |
DOI | 10.3233/JAD-151200 |
Alternate Journal | J. Alzheimers Dis. |
PubMed ID | 26967226 |