title: Inhibiting amyloid β-protein assembly: Size-activity relationships among grape seed-derived polyphenols.
abstract: Epidemiological evidence that red wine consumption negatively correlates with risk of Alzheimer's disease has led to experimental studies demonstrating that grape seed extracts inhibit the aggregation and oligomerization of Aβ in vitro and ameliorate neuropathology and behavioral deficits in a mouse model of Alzheimer's disease. The active agent in the extracts is a mixed population of polyphenolic compounds. To evaluate the relative potency of each of these compounds, HPLC was used to fractionate the mixture into monomers, dimers, and oligomers. Each fraction was analyzed for its effect on Aβ conformational dynamics (circular dichroism), oligomerization (zero-length photochemical cross-linking), aggregation kinetics (Thioflavin T fluorescence), and morphology (electron microscopy). The relative activities of each fraction were determined on the basis of molar concentration (mol/L) or mass concentration (g/L). When molar concentration, the number concentration of each polyphenolic compound, was considered, the oligomer fraction was the most potent inhibitor of Aβ oligomerization and aggregation. However, when mass concentration, the number concentration of phenolic groups, was considered, monomers were the most potent inhibitors. To understand these ostensibly contradictory results, a model of polyphenol:Aβ complexation was developed. This model, which was found to be consistent with published X-ray crystallographic studies, offers an explanation for the effects of functional group polyvalency on inhibitor activity. Our data emphasize the importance of an in-depth understanding of the mechanism(s) underlying 'concentration dependence' in inhibitor systems involving polyfunctional agents.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Hayden
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.|Medical Scientist Training Program, Neuroscience Interdepartmental Ph.D. Program, University of California, Los Angeles, California, USA.
authors.forename: Ghiam
authors.initials: G
authors.lastname: Yamin
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Shiela
authors.initials: S
authors.lastname: Beroukhim
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Benson
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kibalchenko
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York, USA.
authors.forename: Lap
authors.initials: L
authors.lastname: Ho
authors.affiliation: Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York, USA.|Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York, USA.|Geriatric Research, Education and Clinical Center (GRECC), James J. Peters Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, New York, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York, USA.|Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York, USA.|Geriatric Research, Education and Clinical Center (GRECC), James J. Peters Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, New York, USA.
authors.forename: Giulio M
authors.initials: GM
authors.lastname: Pasinetti
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.|Molecular Biology Institute (MBI), and Brain Research Institute (BRI), David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000648:ultrastructure; D000818:Animals; D052160:Benzothiazoles; D002942:Circular Dichroism; D003432:Cross-Linking Reagents; D005456:Fluorescent Dyes; D051379:Mice; D008958:Models, Molecular; D008970:Molecular Weight; D016874:Neurofibrillary Tangles / Q000473:pathology; D059808:Polyphenols / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D012639:Seeds / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles; D027843:Vitis / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D003432:Cross-Linking Reagents; D005456:Fluorescent Dyes; D059808:Polyphenols; D013844:Thiazoles; C009462:thioflavin T
keywords: Alzheimer's disease; amyloid β-protein (Aβ); grape seeds; inhibitors; oligomers; polyphenols