Low Brain Levels of Dietary Polyphenols and Their Conjugates: Reassessing Mechanisms of Alzheimer’s Disease Prevention

Dietary polyphenols such as quercetin, resveratrol, and (-)-epigallocatechin-3-gallate (EGCG) have been shown to be neuroprotective in epidemiologic and experimental studies of Alzheimer’s disease (AD), though clinical evidence remains limited. This re-view highlights the importance of studying glucuronide and sulfate conjugates of these polyphenols, as well as their intestinal microbial metabolites, at bioavailable low na-nomolar concentrations, particularly those that can reach the brain. While many in vitro studies use micromolar concentrations of aglycones, their relevance to understanding neuroprotection is debated. Although polyphenols are redox-sensitive, their direct antioxidant or prooxidant roles may be limited at nanomolar levels, and reactive oxidation products have not been detected in tissues. Instead, their neuroprotective effects appear to be mediated by high-affinity interactions with molecular targets, such as the 67-kDa laminin receptor (67LR). This receptor binds both aglycones and conjugates at low na-nomolar concentrations via a peptide G region containing glycosaminoglycan and palindromic sequences. The same region also binds the prion-amyloid-β complex, sug-gesting that polyphenols could antagonize amyloid-β binding and prevent its neurotoxicity. The peptide G region may also act as a redox sensor. Polyphenol binding to 67LR activates cAMP signaling and downstream neuroprotective pathways involving CREB, SIRT1, and protein phosphatase 2A. Additionally, nanomolar concentrations of resveratrol and quercetin inhibit quinone reductase 2, an enzyme linked to cognitive decline and elevated in AD. Given their low bioavailability in the brain and distinct molecular targets, combining multiple polyphenols at low doses may yield additive and synergistic effects, enhance efficacy, and minimize potential toxicity in preventing AD.