Urolithin A (UA), a metabolite produced from dietary ellagic acid (EA) in the gut, has been demonstrated extend lifespan and healthspan in C. elegans and to be neuroprotective in proteotoxic models of Alzheimer's disease (AD). We have recently shown that UA acts as a potent antagonist of the farnesoid X receptor (FXR). FXR is a bile acid receptor whose traditional role is in the maintenance of lipid homeostasis in the gut and liver, but recently found in brain neurons which undergo neurodegeneration in AD. We discovered that in its capacity as an FXR antagonist, UA results in increased neuronal expression of the master regulator of autophagy transcription factor EB (TFEB). Up-regulation of TFEB has been demonstrated to increase C. elegans lifespan and to protect against neurodegeneration in in vivo neurodegenerative disease models. In response to PAR- 18-596, we propose to determine: (1) the impact of systemic administration of UA on modulation of FXR activity and downstream TFEB-mediated autophagy within brain neurons impacted in AD and whether this can protect against proteotoxic AD phenotypes in vivo and (2) whether age-related reductions in production of UA by the gut microbiota can be restored via introduction of a youthful microbiome and result in increased neuroprotection. Results from these studies, if successful, would further our understanding of how interactions between the brain and the gut impact on neurons affected in AD, how age-related changes in metabolite production in the gut affect this process, and if reinstating a more youthful microbiome restores gut-brain signaling and protects brain neurons.
Age-related changes in the gut microbiome can influence the production of metabolites recently shown to play a yet-to-be-defined neuroprotective role in Alzheimer's disease (AD) models. We propose to identify the mechanisms underlying neuroprotection elicited by one such metabolite, urolithin A (UA) and determine whether age-related reductions in its production in the gut can be restored by introduction of a more youthful microbiome and result in increased neuroprotection in older animals.