TY - JOUR
T1 - Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer's Disease
AU - The Alzheimer's Disease Metabolomics Consortium
AU - Baloni, Priyanka
AU - Funk, Cory C.
AU - Yan, Jingwen
AU - Yurkovich, James T.
AU - Kueider-Paisley, Alexandra
AU - Nho, Kwangsik
AU - Heinken, Almut
AU - Jia, Wei
AU - Mahmoudiandehkordi, Siamak
AU - Louie, Gregory
AU - Saykin, Andrew J.
AU - Arnold, Matthias
AU - Kastenmüller, Gabi
AU - Griffiths, William J.
AU - Thiele, Ines
AU - Kaddurah-Daouk, Rima
AU - Doraiswamy, P. Murali
AU - Blach, Colette
AU - Moseley, Arthur
AU - Thompson, J. Will
AU - Mahmoudiandehkhordi, Siamak
AU - Welsh-Balmer, Kathleen
AU - Plassman, Brenda
AU - Saykin, Andrew
AU - Bhattacharyya, Sudeepa
AU - Han, Xianlin
AU - Baillie, Rebecca
AU - Fiehn, Oliver
AU - Barupal, Dinesh
AU - Meikle, Peter
AU - Mazmanian, Sarkis
AU - Kling, Mitchel
AU - Shaw, Leslie
AU - Trojanowski, John
AU - Toledo, Jon
AU - van Duijin, Cornelia
AU - Hankemier, Thomas
AU - Funk, Cory
AU - Wishart, David
AU - Brinton, Roberta
AU - Chang, Rui
AU - Farrer, Lindsay
AU - Au, Rhoda
AU - Qiu, Wendy
AU - Würtz, Peter
AU - Mangravite, Lara
AU - Krumsiek, Jan
AU - Newman, John
AU - Zhang, Bin
AU - Moreno, Herman
N1 - Publisher Copyright: © 2020 The Authors
PY - 2020/11/17
Y1 - 2020/11/17
N2 - 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. 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.
AB - 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. 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.
KW - Alzheimer's disease
KW - bile acids
KW - cholesterol metabolism
KW - genome-scale metabolic models
KW - metabolomics
KW - transcriptional regulatory networks
KW - transcriptomics
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U2 - 10.1016/j.xcrm.2020.100138
DO - 10.1016/j.xcrm.2020.100138
M3 - Article
C2 - 33294859
SN - 2666-3791
VL - 1
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 8
M1 - 100138
ER -