Quercetin activates AMP-activated protein kinase by reducing PP2C expression protecting old mouse brain against high cholesterol-induced neurotoxicity.
It is known that a high-cholesterol diet induces oxidative stress, inflammatory response, and beta-amyloid (Abeta) accumulation in mouse brain, resulting in neurodegenerative changes. Quercetin, a naturally occurring flavonoid, has been reported to possess numerous biological activities beneficial to health. Our previous studies have demonstrated that quercetin protects mouse brain against D-galactose-induced oxidative damage. Against this background, we evaluated the effect of quercetin on high-cholesterol-induced neurotoxicity in old mice and explored its potential mechanism. Our results showed that oral administration of quercetin significantly improved the behavioural performance of high-cholesterol-fed old mice in both a step-through test and the Morris water maze task. This is at least in part caused by decreasing ROS and protein carbonyl levels and restoring Cu--Zn superoxide dismutase (Cu, Zn-SOD) activity. Furthermore, quercetin also significantly activated the AMP-activated protein kinase (AMPK) via down-regulation of protein phosphatase 2C (PP2C), which reduced the integral optical density (IOD) of activated microglia cells and CD11b expression, down-regulated iNOS and cyclooxygenase-2 (COX-2) expression, and decreased IL-1beta, IL-6, and TNF-alpha expression in the brains of high-cholesterol-fed old mice through the suppression of NF-kappaB p65 nuclear translocation. Moreover, AMPK activation significantly increased 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and acetyl-CoA carboxylase (ACC) phosphorylation and reduced fatty acid synthase (FAS) expression in the brains of high-cholesterol-fed old mice, which reduced cholesterol levels, down-regulated cholesterol 24-hydroxylase (CYP46A1) and beta-amyloid converting enzyme 1 (BACE1) expression, decreased eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation, and lowered Abeta deposits. However, the neuroprotective effect of quercetin was weakened by intraperitoneal injection of compound C, an AMPK inhibitor. These results suggest that AMPK activated by quercetin may be a potential target to enhance the resistance of neurons to age-related diseases.
Lu
Jun
J
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Xuzhou Normal University, Xuzhou 221116, Jiangsu Province, P R China.
Wu
Dong-Mei
DM
Zheng
Yuan-Lin
YL
Hu
Bin
B
Zhang
Zi-Feng
ZF
Shan
Qun
Q
Zheng
Zi-Hui
ZH
Liu
Chan-Min
CM
Wang
Yong-Jian
YJ
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000633:toxicity*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D018782:Maze Learning; D051379:Mice; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D050050:Protein Carbonylation / Q000187:drug effects; D000071636:Protein Phosphatase 2C; D011794:Quercetin / Q000494:pharmacology* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism
D002791:Cholesterol, Dietary; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D011794:Quercetin; D055372:AMP-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C