PMID- 26967226
OWN - NLM
STAT- MEDLINE
DCOM- 20161229
LR  - 20170113
IS  - 1875-8908 (Electronic)
IS  - 1387-2877 (Linking)
VI  - 51
IP  - 4
DP  - 2016
TI  - Metformin Facilitates Amyloid-beta Generation by beta- and gamma-Secretases via Autophagy 
      Activation.
PG  - 1197-208
LID - 10.3233/JAD-151200 [doi]
AB  - 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(R)) increased 
      the generation of amyloid-beta (Abeta), one of the major pathological hallmarks of AD, 
      by promoting beta- and gamma-secretase-mediated cleavage of amyloid-beta protein precursor 
      (AbetaPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome 
      accumulation in Tg6799 AD model mice. Extremely high gamma-secretase activity was 
      also detected in autophagic vacuoles, apparently a novel site of Abeta peptide 
      generation. Together, these data suggest that metformin-induced accumulation of 
      autophagosomes resulted in increased gamma-secretase activity and Abeta 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 AbetaPP processing 
      in autophagosomes.
FAU - Son, Sung Min
AU  - Son SM
AD  - Department of Biochemistry & Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, Korea.
AD  - Neuroscience Research Institute, Seoul National University College of Medicine, 
      Seoul, Korea.
FAU - Shin, Hong-Joon
AU  - Shin HJ
AD  - Department of Biochemistry & Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, Korea.
FAU - Byun, Jayoung
AU  - Byun J
AD  - Department of Biochemistry & Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, Korea.
FAU - Kook, Sun Young
AU  - Kook SY
AD  - Department of Biochemistry & Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, Korea.
FAU - Moon, Minho
AU  - Moon M
AD  - Department of Biochemistry & Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, Korea.
FAU - Chang, Yu Jin
AU  - Chang YJ
AD  - Department of Biochemistry & Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, Korea.
FAU - Mook-Jung, Inhee
AU  - Mook-Jung I
AD  - Department of Biochemistry & Biomedical Sciences, Seoul National University 
      College of Medicine, Seoul, Korea.
AD  - Neuroscience Research Institute, Seoul National University College of Medicine, 
      Seoul, Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Alzheimers Dis
JT  - Journal of Alzheimer's disease : JAD
JID - 9814863
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Hypoglycemic Agents)
RN  - 9100L32L2N (Metformin)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
SB  - IM
MH  - Alzheimer Disease/drug therapy/*metabolism
MH  - Amyloid Precursor Protein Secretases/*metabolism
MH  - Amyloid beta-Peptides/*metabolism
MH  - Amyloid beta-Protein Precursor/genetics
MH  - Animals
MH  - Autophagy/*drug effects
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Hypoglycemic Agents/*pharmacology/therapeutic use
MH  - Lysosomes/drug effects/metabolism/ultrastructure
MH  - Metformin/pharmacology/*therapeutic use
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Microscopy, Electron
MH  - Mutation/genetics
MH  - Neuroblastoma/pathology
MH  - Signal Transduction/drug effects
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - amyloid-beta peptides
OT  - amyloid-beta protein precursor
OT  - autophagy
OT  - metformin
EDAT- 2016/03/12 06:00
MHDA- 2016/12/31 06:00
CRDT- 2016/03/12 06:00
PHST- 2016/03/12 06:00 [entrez]
PHST- 2016/03/12 06:00 [pubmed]
PHST- 2016/12/31 06:00 [medline]
AID - JAD151200 [pii]
AID - 10.3233/JAD-151200 [doi]
PST - ppublish
SO  - J Alzheimers Dis. 2016;51(4):1197-208. doi: 10.3233/JAD-151200.