title: Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation.
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.
authors.affiliation: Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.|Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Son
authors.affiliation: Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hong-Joon
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Byun
authors.affiliation: Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kook
authors.affiliation: Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Moon
authors.affiliation: Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Chang
authors.affiliation: Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.|Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007004:Hypoglycemic Agents; D008687:Metformin; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; amyloid-β peptides; amyloid-β protein precursor; autophagy; metformin