TY - JOUR
T1 - Flavonoid-Derived Human Phenyl-γ-Valerolactone Metabolites Selectively Detoxify Amyloid-β Oligomers and Prevent Memory Impairment in a Mouse Model of Alzheimer's Disease
AU - Ruotolo, Roberta
AU - Minato, Ilaria
AU - La Vitola, Pietro
AU - Artioli, Luisa
AU - Curti, Claudio
AU - Franceschi, Valentina
AU - Brindani, Nicoletta
AU - Amidani, Davide
AU - Colombo, Laura
AU - Salmona, Mario
AU - Forloni, Gianluigi
AU - Donofrio, Gaetano
AU - Balducci, Claudia
AU - Del Rio, Daniele
AU - Ottonello, Simone
N1 - © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2020/3
Y1 - 2020/3
N2 - SCOPE: Amyloid-β oligomers (AβO) are causally related to Alzheimer's disease (AD). Dietary natural compounds, especially flavonoids and flavan-3-ols, hold great promise as potential AD-preventive agents but their host and gut microbiota metabolism complicates identification of the most relevant bioactive species. This study aims to investigate the ability of a comprehensive set of phenyl-γ-valerolactones (PVL), the main circulating metabolites of flavan-3-ols and related dietary compounds in humans, to prevent AβO-mediated toxicity.METHODS AND RESULTS: The anti-AβO activity of PVLs is examined in different cell model systems using a highly toxic β-oligomer-forming polypeptide (β23) as target toxicant. Multiple PVLs, and particularly the monohydroxylated 5-(4'-hydroxyphenyl)-γ-valerolactone metabolite [(4'-OH)-PVL], relieve β-oligomer-induced cytotoxicity in yeast and mammalian cells. As revealed by atomic force microscopy (AFM) and other in vitro assays, (4'-OH)-PVL interferes with AβO (but not fibril) assembly and actively remodels preformed AβOs into nontoxic amorphous aggregates. In keeping with the latter mode of action, treatment of AβOs with (4'-OH)-PVL prior to brain injection strongly reduces memory deterioration as well as neuroinflammation in a mouse model of AβO-induced memory impairment.CONCLUSION: PVLs, which have been validated as biomarkers of the dietary intake of flavan-3-ols, lend themselves as novel AβO-selective, candidate AD-preventing compounds.
AB - SCOPE: Amyloid-β oligomers (AβO) are causally related to Alzheimer's disease (AD). Dietary natural compounds, especially flavonoids and flavan-3-ols, hold great promise as potential AD-preventive agents but their host and gut microbiota metabolism complicates identification of the most relevant bioactive species. This study aims to investigate the ability of a comprehensive set of phenyl-γ-valerolactones (PVL), the main circulating metabolites of flavan-3-ols and related dietary compounds in humans, to prevent AβO-mediated toxicity.METHODS AND RESULTS: The anti-AβO activity of PVLs is examined in different cell model systems using a highly toxic β-oligomer-forming polypeptide (β23) as target toxicant. Multiple PVLs, and particularly the monohydroxylated 5-(4'-hydroxyphenyl)-γ-valerolactone metabolite [(4'-OH)-PVL], relieve β-oligomer-induced cytotoxicity in yeast and mammalian cells. As revealed by atomic force microscopy (AFM) and other in vitro assays, (4'-OH)-PVL interferes with AβO (but not fibril) assembly and actively remodels preformed AβOs into nontoxic amorphous aggregates. In keeping with the latter mode of action, treatment of AβOs with (4'-OH)-PVL prior to brain injection strongly reduces memory deterioration as well as neuroinflammation in a mouse model of AβO-induced memory impairment.CONCLUSION: PVLs, which have been validated as biomarkers of the dietary intake of flavan-3-ols, lend themselves as novel AβO-selective, candidate AD-preventing compounds.
U2 - 10.1002/mnfr.201900890
DO - 10.1002/mnfr.201900890
M3 - Article
C2 - 31914208
VL - 64
SP - e1900890
JO - Molecular Nutrition and Food Research
JF - Molecular Nutrition and Food Research
SN - 1613-4125
IS - 5
ER -