PMID- 31450493
OWN - NLM
STAT- MEDLINE
DCOM- 20201105
LR  - 20211204
IS  - 1875-8908 (Electronic)
IS  - 1387-2877 (Linking)
VI  - 71
IP  - 3
DP  - 2019
TI  - Resveratrol and Metformin Recover Prefrontal Cortex AMPK Activation in 
      Diet-Induced Obese Mice but Reduce BDNF and Synaptophysin Protein Content.
PG  - 945-956
LID - 10.3233/JAD-190123 [doi]
AB  - BACKGROUND: Obesity, insulin resistance, and type 2 diabetes are established risk 
      factors for the development of Alzheimer's disease (AD). Given this connection, 
      two drugs, metformin (MET) and resveratrol (RESV), are considered for the 
      clearance of amyloid-beta peptides through AMPK-mediated activation of autophagy. 
      However, overactivation of AMPK observed in late-stage AD brains and 
      relationships between AMPK and neurogenesis (through mTORC1 inhibition), 
      questions treatment with these drugs. OBJECTIVE: To examine if MET and/or RESV 
      supplementation activates brain AMPK, regulates markers of autophagy, and affects 
      markers of neuronal health/neurogenesis. METHODS: 8-week-old male C57BL/6J mice 
      were fed a low (N = 12; 10% kcal fat; LFD) or high fat diet (N = 40; 60% kcal 
      fat; HFD) for 9 weeks to induce insulin resistance and obesity. HFD mice were 
      then treated with/without MET (250 mg/kg/day), RESV (100 mg/kg/day), or COMBO 
      (MET: 250 mg/kg/day, RESV: 100 mg/kg/day) for 5 weeks. Hippocampus and prefrontal 
      cortex were extracted for western blotting analysis. RESULTS: Cortex AMPK (T172) 
      and raptor (S792, the regulatory subunit of mTORC1) phosphorylation were 
      upregulated following RESV, COMBO treatments. mTOR (S2448) and ULK1 (S555) 
      activation was seen following MET, COMBO and RESV, COMBO treatments, 
      respectively, in the cortex and hippocampus. p62 content was decreased following 
      RESV, COMBO, with LC3 content being increased following RESV treatment in the 
      cortex. Brain derived neurotropic factor (BDNF) was significantly decreased 
      following RESV, COMBO, and synaptophysin following all treatment in the cortex. 
      CONCLUSION: These results demonstrate that while treatments upregulated markers 
      of autophagy in the prefrontal cortex, reductions in neuronal health markers 
      question the efficacy of AMPK as a therapy for AD.
FAU - Yang, Alex J T
AU  - Yang AJT
AD  - Department of Health Sciences, Brock University, St. Catharines, ON, Canada.
FAU - Frendo-Cumbo, Scott
AU  - Frendo-Cumbo S
AD  - Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
AD  - Department of Physiology, University of Toronto, Toronto, ON, Canada.
FAU - MacPherson, Rebecca E K
AU  - MacPherson REK
AD  - Department of Health Sciences, Brock University, St. Catharines, ON, Canada.
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 (Antioxidants)
RN  - 0 (Bdnf protein, mouse)
RN  - 0 (Blood Glucose)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Synaptophysin)
RN  - 0 (Syp protein, mouse)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - Q369O8926L (Resveratrol)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Animals
MH  - Antioxidants/*pharmacology
MH  - Autophagy/drug effects
MH  - Blood Glucose/metabolism
MH  - Brain-Derived Neurotrophic Factor/biosynthesis
MH  - Diet, High-Fat
MH  - Enzyme Activation/drug effects
MH  - Hypoglycemic Agents/*pharmacology
MH  - Insulin Resistance
MH  - Male
MH  - Metformin/*pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Obesity/*enzymology/metabolism
MH  - Prefrontal Cortex/*enzymology
MH  - Resveratrol/*pharmacology
MH  - Synaptophysin/biosynthesis
MH  - TOR Serine-Threonine Kinases/biosynthesis/genetics
OTO - NOTNLM
OT  - Autophagy
OT  - BDNF
OT  - metformin
OT  - resveratrol
OT  - synaptophysin
EDAT- 2019/08/28 06:00
MHDA- 2020/11/06 06:00
CRDT- 2019/08/28 06:00
PHST- 2019/08/28 06:00 [pubmed]
PHST- 2020/11/06 06:00 [medline]
PHST- 2019/08/28 06:00 [entrez]
AID - JAD190123 [pii]
AID - 10.3233/JAD-190123 [doi]
PST - ppublish
SO  - J Alzheimers Dis. 2019;71(3):945-956. doi: 10.3233/JAD-190123.