Identification of brain‐targeted bioactive dietary quercetin‐3‐O‐glucuronide as a novel intervention for Alzheimer's disease

Previous studies indicate polyphenol intake from moderate consumption of red wines may lower relative risk of developing Alzheimer's disease (AD). We assessed accumulations of polyphenols in rat brain following oral dosage with Cabernet Sauvignon and tested brain‐targeted polyphenols for potential beneficial AD disease‐modifying activities. We demonstrated that the brain‐targeted polyphenol metabolite quercetin‐3‐O‐glucuronide significantly reduced generation of β‐amyloid (Aβ) peptides compared to control by primary neuron cultures from the Tg2576 AD mouse model. Using photo‐induced cross‐lining of unmodified proteins (PICUP) technique in vitro, we found quercetin‐3‐O‐glucuronide capable of interfering with the initial protein‐protein interaction of Aβ 1–40 and Aβ 1–42 , necessary for the formation of neurotoxic oligomeric Aβ species. Quercetin‐3‐O‐glucuronide treatment significantly improved AD‐type deficits in hippocampal formation, basal synaptic transmission, and long‐term potentiation. Brain‐targeted quercetin‐3‐O‐glucuronide may modulate multiple independent AD disease modifying mechanisms and thus may contribute to benefits of dietary supplementation with red wines as an effective intervention for AD.