Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease

• Published in: Cell reports. Medicine 2020-11, Vol.1 (8), p.100138, Article 100138
• Main Authors: Baloni, Priyanka, Funk, Cory C., Yan, Jingwen, Yurkovich, James T., Kueider-Paisley, Alexandra, Nho, Kwangsik, Heinken, Almut, Jia, Wei, Mahmoudiandehkordi, Siamak, Louie, Gregory, Saykin, Andrew J., Arnold, Matthias, Kastenmüller, Gabi, Griffiths, William J., Thiele, Ines, Kaddurah-Daouk, Rima, Doraiswamy, P. Murali, Blach, Colette, Moseley, Arthur, Thompson, J. Will, Mahmoudiandehkhordi, Siamak, Welsh-Balmer, Kathleen, Plassman, Brenda, Saykin, Andrew, Bhattacharyya, Sudeepa, Han, Xianlin, Baillie, Rebecca, Fiehn, Oliver, Barupal, Dinesh, Meikle, Peter, Mazmanian, Sarkis, Kling, Mitchel, Shaw, Leslie, Trojanowski, John, Toledo, Jon, van Duijin, Cornelia, Hankemier, Thomas, Price, Nathan, Funk, Cory, Wishart, David, Brinton, Roberta, Chang, Rui, Farrer, Lindsay, Au, Rhoda, Qiu, Wendy, Würtz, Peter, Mangravite, Lara, Krumsiek, Jan, Newman, John, Zhang, Bin, Moreno, Herman, Price, Nathan D.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; bile acids; Bile Acids and Salts - metabolism; Brain - metabolism; Cholesterol - metabolism; Cognitive Dysfunction - metabolism; genome-scale metabolic models; Humans; Lipid Metabolism - physiology; Lipogenesis - physiology; Metabolic Networks and Pathways - physiology; metabolomics; Metabolomics - methods; transcriptional regulatory networks; Transcriptome - physiology; transcriptomics
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2020.100138

Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain. These findings motivate further research into bile acid metabolism in AD to elucidate their possible connection to cognitive decline. [Display omitted] Altered cholesterol and bile acid metabolism linked to Alzheimer disease (AD)Evidence for alternative bile acid pathway genes expression in post-mortem brainsMetabolomics analysis shows secondary bile acids associated with cognitive declineGenome-scale metabolic networks of brain regions identify reactions linked to AD Baloni et al. use a systems biology approach to identify alterations in cholesterol and bile acid metabolism in Alzheimer disease (AD). Expression of alternative bile acid and neural cholesterol clearance pathway along with transporters of taurine and bile acids suggest the role of the gut-brain axis in AD.