New mechanistic insights into how the gut metabolite urolithin A extends lifespan and prevents AD

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PROJECT SUMMARY/ABSTRACT The parent award proposes to assess the potential neuroprotective effects of the gut metabolite urolithin A (UA) in the 3xAD Tg model of Alzheimer’s disease (AD). Aim 3 of the grant centers on the hypothesis that reductions in age-related gut microbiota involved in the production of UA from its dietary precursor ellagic acid may contribute to increased neuropathology associated with the 3xAD model and can be prevented by restoration of a more youthful microbiome. In addition to its direct impact on neurons (the subject of the parent grant), UA potentially may also have indirect effects via its ability to maintain gut integrity and function which can have ‘knock on’ effects on neuronal integrity via the gut-brain axis. In order to get a better handle on potential mechanisms that may underlie gut inflammation and influence the development of AD-related neuropathology in these mice, we initiated a collaboration with Dr. Dan Winer at the Buck, an expert on the role of the adaptive immune system in controlling metabolic tissue inflammation. Bacterial profiling was performed and revealed a clear difference in the levels of pro-inflammatory bacteria in the AD mouse colon, coinciding with a striking enrichment in the level of CD4+Tbet+ (Th1) immune cell populations previously linked to reduced gut barrier function and dysbiosis. Additional studies as part of the funded parent grant demonstrated that UA-fed 3xAD mice show significant reductions in Aß neuropathology and improvement in behavioral deficits. As postulated in the original grant, this may be in part due to direct effects on neuronal cells in the CNS. However, it may also involve the compound’s ability to maintain gut integrity and function and reduce gut inflammation. The purpose of this supplement is to provide us with funds to allow us to determine whether UA’s neuroprotective effects are due in part to its ability to influence gut health.