Quercetin activates AMP‐activated protein kinase by reducing PP2C expression protecting old mouse brain against high cholesterol‐induced neurotoxicity

Abstract

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.

Quercetin ameliorates inflammation in CA1 hippocampal region in aged triple transgenic Alzheimer´s disease mice model.

“…Our findings suggest that the quercetin treatment induced an anti-inflammatory response confirming previous studies where the compound decreases the production of inflammatory mediators such as iNOS, NO, COX-2, PGE 2 , and IL-1β and reduces the activation of microglia and astrocytes (30)(31)(32)(33). Furthermore, quercetin contributes to the reduction of oxidative stress, since it increases the production of antioxidant enzymes in astrocytes, microglia and neurons (34,35).…”

Troxerutin Counteracts Domoic Acid–Induced Memory Deficits in Mice by Inhibiting CCAAT/Enhancer Binding Protein β–Mediated Inflammatory Response and Oxidative Stress

“…In addition, several studies have demonstrated that the suppression of TNF-a production reduces KA-mediated excitotoxicity (21,22); however, it is not yet clear how the C/EBP b-TNF-a signaling axis medi-ates excitotoxic brain damage. Our previous reports have demonstrated that chronic brain inflammation can impair the learning and memory abilities of mice (15,(23)(24)(25)(26). Thus, we hypothesized that an abnormal change of the C/EBP b-TNF-a signaling axis could be involved in the pathophysiological processes of DAinduced cognitive deficits.…”

Targeting AMPK for Therapeutic Intervention in Type 2 Diabetes

“…For example, LKB1 is particularly important to activate AMPK in skeletal muscle, whereas CaMKK is crucial in the brain (Ronnett et al, 2009). On the other hand, TNF alters AMPK activation by modulating the synthesis of PP2C (Lu et al, 2010;Steinberg et al, 2006). Aside from the rapid control of AMPK activation by phosphorylation, changes in the expression of subunit genes or the turnover of AMPK subunits can help to fine tune AMPK activity in some tissues (Barry et al, 2010;Fukuyama et al, 2007;Hallows et al, 2006;Qi et al, 2008;Niesler et al, 2007;Steinberg et al, 2003).…”