Deciphering the effect of human microbiota on Alzheimer's disease using C. elegans models of protein conformational diseases

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Alzheimer’s disease (AD) is a fatal neurodegenerative disorder characterized by a progressive loss of memory and cognitive function due to protein misfolding and aggregation, a common feature among protein conformational diseases (PCDs). The exact factors that influence PCDs are not known; however, recent evidence suggests that bacteria may contribute to the pathogenesis of AD and other neurodegenerative diseases. To better understand the influence of bacteria on protein homeostasis (proteostasis), we are studying the effects of bacterial colonization of the Caenorhabditis elegans gut on protein aggregation in the intestine and other tissues. In a pilot screen of over 60 strains, we identified bacteria that can either increase or decrease protein aggregation not only in the intestine but throughout other tissues, including muscle, neurons, and gonad. We found that the bacteria that suppress protein aggregation have something in common—they produce butyrate. In follow-up experiments, we demonstrated that both exogenous and endogenous butyrate suppressed bacteria- mediated protein aggregation. These results suggest that intestinal bacteria affect host proteostasis and can potentially contribute to the pathogenesis of AD. Collectively, our preliminary data reveal a possible causative role for bacteria in diseases that are characterized by protein aggregation. As such, we propose to further investigate the effect of bacteria on proteostasis using C. elegans models by: (I) determining the impact of intestinal colonization by all human microbiome bacterial isolates on host proteostasis and pathogenesis of AD, and (II) observing the effect of exogenous and endogenous butyrate on bacteria that enhance protein aggregation. Deciphering the effect that bacteria have on host proteostasis will ultimately provide a basis for the development of prophylactics, therapeutics, and biomarkers.