Red wine (poly)phenols supplementation reduces amyloid-beta (aβ) pathology in APP/PS1 mice model: Possible implications of gut-brain axis explored by untargeted fecal metabolomics.

Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder influenced by genetics and lifestyle. The Mediterranean diet, especially moderate red wine (RW) intake, may offer neuroprotection through (poly)phenols acting on amyloid pathology, neuroinflammation, and the gut-brain axis. This study evaluated RW and dealcoholized red wine (DRW) effects on hippocampal Aβ in APP/PS1 mice. DRW reduced Aβ40 and Aβ42, levels, with males showing greater sensitivity. Untargeted fecal metabolomics revealed DRW modulates sex-specific metabolic pathways. In males, enriched lipid and mitochondrial pathways were observed, while in females, DRW impacted broader networks, including nucleotide, TCA cycle, and hormone metabolism. Guanosine and estradiol phenylpropionate correlated with Aβ42 in females, indicating sex-specific mechanisms. Findings suggest RW components may attenuates AD pathology via amyloid reduction and metabolic modulation, being dose and sex dependent. This highlights the potential of gut-derived metabolites in mediating (poly)phenol-driven neuroprotection and the importance of personalized dietary approaches to AD.