Promoting circadian rhythms to optimize gut-to-brain signaling for Alzheimer's disease

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Project Summary Alzheimer’s disease (AD) is the leading cause of neurodegeneration worldwide and one of the leading causes of death in the United States. AD patients have reduced gut microbiome population diversity and altered microbiota species composition. However, little is known about the relationship between microbiome alterations and the onset or progression of AD including gut-to-brain signaling. To investigate these interactions, we propose using the well-characterized genetic model of AD, Drosophila melanogaster (fruit fly) to test the impact of genetic or environmental circadian rhythm disruptions (CRD) on the microbiome population, and the onset and severity of the cognitive decline in AD. In our study, we intend to address the effects of dysbiosis on AD progression, and mechanistic aspects of genetic manipulation in specific regions of the nervous system on the microbiota composition for gut-to-brain accesses. Moreover, to restore AD-induced dysbiosis and CRD-mediated metabolic dysregulation, we will impose time-restricted feeding (TRF), an effective behavioral intervention in which food is provided to flies only during the active cycle. The time-series microbiome and metagenomic analyses will be performed under ad lib fed (ALF) and TRF to further recognize the mechanistic basis of microbiome-induced AD. The functional significance of microbiota and altered signaling will be tested in vivo by expressing genetic gain-of-function and loss-of-function approaches. Moreover, probiotics are known to influence human health and will be tested for their impact on fly AD models. Our novel in vivo genetic-transgenic Drosophila disease model coupled with tissue-specific functional, cytological metabolic, and microbiomes will generate unbiased/mechanistic insights into gut-to-brain signaling for AD. The following aims will be used to test our hypothesis and explore the role of the microbiome in AD, including factors that optimized AD that mitigates dysbiosis. 1. Determine whether depletion of gut microbiota results in AD-induced neurodegeneration and TRF retain healthy microbiome in humanized Drosophila AD models. 2. Determine how dysbiosis-induced gut-to-brain signaling occurs in Drosophila models of AD. 3. Time-series analysis of Drosophila microbiome in AD model under ALF and TRF, and their validation in vivo, including testing human microbiome and probiotic for therapeutic treatments. Successful completion of this project will provide a deeper molecular understanding of the microbiome association in promoting circadian rhythm via TRF-optimized gut-to-brain signaling for AD. Overall, our complementary and innovative approaches are suitable for PAR-22-211 and will address the molecular basis of dysbiosis in AD and dysmetabolism TRF is beneficial in the context of AD by promoting circadian rhythms and a healthy microbiome, along with also evaluating therapeutic probiotic treatments. Additionally, this research will assess the efficacy of a behavioral intervention that would have a high potential for adoption in humans.