Gut Microbiota-derived Bile Acids Promote Gamma-secretase Activity Through Interactions with Nicastrin Subunits

Alzheimer's disease (AD) has emerged as a progressively pervasive neurodegenerative disorder worldwide. Bile acids, synthesized in the liver and modified by the gut microbiota, play pivotal roles in diverse physiological processes, and their dysregulation in individuals with AD has been well-documented. However, the protein targets associated with microbiota-derived bile acids in AD have received limited attention. To address this gap, we conducted comprehensive thermal proteomic analyses to unravel and comprehend the protein targets affected by microbiota-derived bile acids in AD. Our investigation identified sixty-five unique proteins as potential targets of deoxycholic acid (DCA), a primary component of the bile acid pool originating from the gut microbiota. Particularly noteworthy among these proteins were Nicastrin and Casein kinase 1 epsilon. We found that DCA, through its interaction with the Nicastrin subunit of {\gamma}-secretase, significantly contributed to the formation of amyloid beta, a key hallmark of AD pathology. Additionally, We observed substantial elevations in the urine levels of four bile acids (DCA, GHCA, GHDCA, and GUDCA) in AD patients compared to healthy controls. Moreover, the ratios of DCA to cholic acid (CA) and glycodeoxycholic acid (GDCA) to DCA were significantly increased in AD patients, indicating aberrations in the biosynthetic pathway responsible for bile acid dehydroxylation. The augmented levels of microbiota-derived bile acids and their altered ratios to primary bile acids exhibited notable associations with AD. Collectively, our findings provide crucial insights into the intricate interplay between microbiota-derived bile acids and the pathogenesis of AD, thereby shedding light on potential therapeutic targets for this debilitating disease.