quercetin-3-o-glucuronide and Alzheimer-Disease

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.. AD mice model built through intracerebroventricular injection of Aβ. Q3G can alleviate brain IR through directly acting on the brain or modulating the gut-brain axis, ultimately to relieve Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line, Tumor; Cognitive Dysfunction; Disease Models, Animal; Gastrointestinal Microbiome; Hippocampus; Humans; Insulin Resistance; Male; Memory Disorders; Mice, Inbred C57BL; Neuroblastoma; Neurons; Neuroprotective Agents; Peptide Fragments; Quercetin; tau Proteins

Epidemiological and preclinical studies indicate that polyphenol intake from moderate consumption of red wines may lower the relative risk for developing Alzheimer's disease (AD) dementia. There is limited information regarding the specific biological activities and cellular and molecular mechanisms by which wine polyphenolic components might modulate AD. We assessed accumulations of polyphenols in the rat brain following oral dosage with a Cabernet Sauvignon red wine and tested brain-targeted polyphenols for potential beneficial AD disease-modifying activities. We identified accumulations of select polyphenolic metabolites in the brain. We demonstrated that, in comparison to vehicle-control treatment, one of the brain-targeted polyphenol metabolites, quercetin-3-O-glucuronide, significantly reduced the generation of β-amyloid (Aβ) peptides by primary neuron cultures generated from the Tg2576 AD mouse model. Another brain-targeted metabolite, malvidin-3-O-glucoside, had no detectable effect on Aβ generation. Moreover, in an in vitro analysis using the photo-induced cross-linking of unmodified proteins (PICUP) technique, we found that quercetin-3-O-glucuronide is also capable of interfering with the initial protein-protein interaction of Aβ(1-40) and Aβ(1-42) that is necessary for the formation of neurotoxic oligomeric Aβ species. Lastly, we found that quercetin-3-O-glucuronide treatment, compared to vehicle-control treatment, significantly improved AD-type deficits in hippocampal formation basal synaptic transmission and long-term potentiation, possibly through mechanisms involving the activation of the c-Jun N-terminal kinases and the mitogen-activated protein kinase signaling pathways. Brain-targeted quercetin-3-O-glucuronide may simultaneously modulate multiple independent AD disease-modifying mechanisms and, as such, may contribute to the benefits of dietary supplementation with red wines as an effective intervention for AD.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anthocyanins; Biological Availability; Brain; Cells, Cultured; Dietary Supplements; Disease Models, Animal; Glucosides; Humans; Male; Mice; Mice, Transgenic; Neuronal Plasticity; Neurons; Neuroprotective Agents; Polyphenols; Protein Multimerization; Quercetin; Rats; Rats, Sprague-Dawley; Signal Transduction; Wine