Flavonoid‐Derived Human Phenyl‐γ‐Valerolactone Metabolites Selectively Detoxify Amyloid‐β Oligomers and Prevent Memory Impairment in a Mouse Model of Alzheimer's Disease

Abstract

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.

Polyphenols in Alzheimer’s Disease and in the Gut–Brain Axis

“…The aryl-γ-valerolactone metabolites also have protective effects against AD, as shown in the mouse AD models [42]. These valerolactones and their secondary metabolites were shown to selectively detoxify Aβ oligomers and thereby prevent memory loss in the mouse AD models [42]. Further metabolism of the valerolactones results in the formation of phenolic or polyphenolic degradation products, such as (hydroxyaryl)valeric acid, (hydroxyaryl)cinnamic acid, (hydroxyaryl)propanoic acid, (hydroxyaryl)acetic acid, and hydroxybenzoic acid derivatives (Figure 3).…”

“…Gut bacterial metabolism of the flavan-3-ols results in the formation of various aryl-γ-valerolactone and arylvaleric acid derivatives, as the major compounds, were originally shown to have protective effects against urinary tract infections, [38][39][40][41]. The aryl-γ-valerolactone metabolites also have protective effects against AD, as shown in the mouse AD models [42]. These valerolactones and their secondary metabolites were shown to selectively detoxify Aβ oligomers and thereby prevent memory loss in the mouse AD models [42].…”

Diet and Mental Health: Review of the Recent Updates on Molecular Mechanisms

“…Similarly, high glycemic load meals and consumption of processed meat products have been associated with the production of inflammatory biomarkers [89,90]. Finally, the previously mentioned phenyl-γ-valerolactones, originating by gut microbiota transformation of flavan-3-ols, may exert their neuroprotective activity in secondary prevention strategies for AD also through an anti-inflammatory mechanism, having been shown to be able to reduce glial over-activation in amyloid-β oligomers-treated mice [72].…”

“…Among these, the chemical rearrangement of flavan-3-ols, one of the most common flavonoid subclasses, has been extensively studied [70]. The main flavan-3-ol colonic metabolites, namely phenyl-γ-valerolactones, have been recently found to be able to cross the blood-brain barrier and be available to the neuronal cell [71], where they may effectively interfere with amyloid-β oligomers assembly, representing a potential novel pharmacological tool to prevent Aβ aggregation and Aβ-induced neurodegeneration in Alzheimer's disease (AD) [72]. Additionally, some more other small colonic metabolites are the object of similar studies, as they have been able to exert anti-inflammatory activity at the neuronal level [73].…”

Phenyl‐γ‐valerolactones and healthy ageing: Linking dietary factors, nutrient biomarkers, metabolic status and inflammation with cognition in older adults (the VALID project)

“…Recently, a paper from our group focused on the putative role of PVLs in counteracting the formation of amyloid‐β oligomers and reducing their cerebral toxic effects (Ruotolo et al . 2020). Genetic mutations and errors in the transcription and translation of the amyloid precursor protein, allow amyloid‐β oligomers to accumulate into the neurons by forming plaques which are considered the basis of the development of neurodegenerative diseases, such as Alzheimer’s disease.…”