Flavonoid-derived human phenyl-γ-valerolactone metabolites selectively detoxify amyloid-β oligomers and prevent memory impairment in a mouse model of Alzheimer's disease

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.