Mechanistic insights into the neuroprotective potential of gut microbiota-derived urolithins in Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, tau pathology, synaptic failure, and progressive neuronal loss. In addition to these classical hallmarks, chronic neuroinflammation, oxidative stress, and mitochondrial dysfunction have gained recognition as central to disease pathogenesis. Dietary polyphenols and their microbial metabolites have emerged as promising modulators of these processes. Among them, urolithins, bioactive gut-derived compounds produced from ellagitannins, exhibit notable neuroprotective potential both in vitro and in vivo. Urolithins readily cross the blood-brain barrier and modulate key pathways implicated in AD, including tau-mediated axonal degeneration, microglial activation, redox imbalance, and impaired mitophagy in cellular and animal models. In the present narrative review, we discuss the mechanistic basis of urolithin's actions in established cellular models and in ageing animal brains, highlighting in vitro and preclinical evidence that positions these metabolites at the intersection of nutrition, microbiota, and neurodegeneration. We propose that targeting urolithin-sensitive pathways may offer a novel, multifaceted strategy against AD-related brain dysfunction and slow disease progression.