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 can induce brain Insulin resistance (IR). Gut microbiome disorder is correlated with inflammation in AD. As of yet, there are no effective treatments clinically. Thus, it is focused 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 Aβ_1-42 and AD cell model developed through the SH-SY5Y cell line and Aβ_1-42 are used to explore the protective effects of Q3G on AD. Neurobehavioral test, brain Insulin signaling pathway, and high-throughput pyrosequencing of 16S rRNA are assessed. Data show that Q3G attenuates neuroinflammation and brain IR in Aβ_1-42 -injected mice and relieves Apoptosis in Aβ_1-42 -treated SH-SY5Y cells by interrupting the downstream Insulin signaling. Q3G ameliorates Aβ accumulation and Tau phosphorylation, restores CREB and BDNF levels in the hippocampus , and reverses Aβ_1-42 -induced cognitive impairment. Besides, Q3G restores Aβ_1-42 -induced reduction of short-chain fatty acids (SCFAs) and gut microbiota dysbiosis.

Conclusion: Q3G can alleviate brain IR through directly acting on the brain or modulating the gut-brain axis, ultimately to relieve Aβ_1-42 -induced cognitive dysfunction.