Quercetin-3-O-Glucuronide Alleviates Cognitive Deficit and Toxicity in Aβ1-42 -Induced AD-Like Mice and SH-SY5Y Cells.

SCOPE Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) related imbalance, tau-hyperphosphorylation, and neuroinflammation, in which Aβ and neuroinflammation could induce brain insulin resistance (IR). Gut microbiome disorder is correlated with inflammation in AD. As of yet, there are no effective treatments clinically. Thus, we focus on the potential benefit of quercetin-3-O-glucuronide (Q3G), a pharmacologically active flavonol glucuronide, on AD treatment by regulating brain IR and the gut microbiome. METHODS AND RESULTS AD mice model built through intracerebroventricular injection of Aβ1-42 and AD cell model developed through the SH-SY5Y cell line and Aβ1-42 were used to explore the protective effects of Q3G on AD. Neurobehavioral test, brain insulin signaling pathway, and high-throughput pyrosequencing of 16S rRNA were assessed. Data showed that Q3G attenuated neuroinflammation and brain IR in Aβ1-42 -injected mice and relieved apoptosis in Aβ1-42 -treated SH-SY5Y cells by interrupting the downstream insulin signaling. Q3G ameliorated Aβ accumulation and Tau phosphorylation, restored CREB and BDNF levels in the hippocampus, and reversed Aβ1-42 -induced cognitive impairment. Besides, Q3G restored Aβ1-42 -induced reduction of short-chain fatty acids and gut microbiota dysbiosis. CONCLUSION Q3G could alleviate brain IR through directly acting on the brain or modulating the gut-brain axis, ultimately to relieve Aβ1-42 -induced cognitive dysfunction. This article is protected by copyright. All rights reserved.