title: Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease.
abstract: 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.
authors.affiliation: Department of Neurology, Mt. Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Lap
authors.initials: L
authors.lastname: Ho
authors.forename: Mario G
authors.initials: MG
authors.lastname: Ferruzzi
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Janle
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Bing
authors.initials: B
authors.lastname: Gong
authors.forename: Tzu-Ying
authors.initials: TY
authors.lastname: Chen
authors.forename: Jessica
authors.initials: J
authors.lastname: Lobo
authors.forename: Bruce
authors.initials: B
authors.lastname: Cooper
authors.forename: Qing Li
authors.initials: QL
authors.lastname: Wu
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Talcott
authors.forename: Susan S
authors.initials: SS
authors.lastname: Percival
authors.forename: James E
authors.initials: JE
authors.lastname: Simon
authors.forename: Giulio Maria
authors.initials: GM
authors.lastname: Pasinetti
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000178:diet therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000872:Anthocyanins / Q000008:administration & dosage / Q000493:pharmacokinetics; D001682:Biological Availability; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005960:Glucosides; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D059808:Polyphenols / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D055503:Protein Multimerization / Q000187:drug effects; D011794:Quercetin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014920:Wine / Q000032:analysis
chemical_list: D016229:Amyloid beta-Peptides; D000872:Anthocyanins; D005960:Glucosides; D018696:Neuroprotective Agents; D059808:Polyphenols; C443401:quercetin 3-O-glucuronide; C458419:malvidin-3-glucoside; D011794:Quercetin