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Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
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Ines Thiele,
Rima Kaddurah-Daouk,
Nathan D. Price,
Rima Kaddurah-Daouk,
Alexandra Kueider-Paisley,
Gregory Louie,
P. Murali Doraiswamy,
Colette Blach,
Arthur Moseley,
J. Will Thompson,
Siamak Mahmoudiandehkhordi,
Kathleen Welsh-Balmer,
Brenda Plassman,
Andrew Saykin,
Kwangsik Nho,
Gabi Kastenmüller,
Matthias Arnold,
Sudeepa Bhattacharyya,
Xianlin Han,
Rebecca Baillie,
Oliver Fiehn,
Dinesh Barupal,
Peter Meikle,
Sarkis Mazmanian,
Mitchel Kling,
Leslie Shaw,
John Trojanowski,
Jon Toledo,
Cornelia van Duijin,
Thomas Hankemier,
Ines Thiele,
Almut Heinken,
Nathan Price,
Cory Funk,
Priyanka Baloni,
Wei Jia,
David Wishart,
Roberta Brinton,
Rui Chang,
Lindsay Farrer,
Rhoda Au,
Wendy Qiu,
Peter Würtz,
Lara Mangravite,
Jan Krumsiek,
John Newman,
Bin Zhang,
Herman Moreno
Cell Reports Medicine, Volume: 1, Issue: 8, Start page: 100138
Swansea University Author:
William Griffiths
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DOI (Published version): 10.1016/j.xcrm.2020.100138
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia, with metabolic dysfunction seen years before the emergence of clinical symptoms. Increasing evidence suggests a role for primary and secondary bile acids, the end-product of cholesterol metabolism, influencing pathophysiology in AD. In this...
| Published in: | Cell Reports Medicine |
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| ISSN: | 2666-3791 |
| Published: |
Elsevier BV
2020
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa55544 |
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| Abstract: |
Alzheimer’s disease (AD) is the leading cause of dementia, with metabolic dysfunction seen years before the emergence of clinical symptoms. Increasing evidence suggests a role for primary and secondary bile acids, the end-product of cholesterol metabolism, influencing pathophysiology in AD. In this study, we analyzed transcriptomes from 2114 post-mortem brain samples from three independent cohorts and identified that the genes involved in the alternative bile acid synthesis pathway were expressed in the brain compared to the classical pathway. These results were supported by targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals. We reconstructed brain region-specific metabolic networks using data from three independent cohorts to assess the role of bile acid metabolism in AD pathophysiology. Our metabolic network analysis suggested that taurine transport, bile acid synthesis and cholesterol metabolism differed in AD and cognitively normal individuals. Using the brain transcriptional regulatory network, we identified putative transcription factors regulating these metabolic genes and influencing altered metabolism in AD. Intriguingly, we find bile acids from the brain metabolomics whose synthesis cannot be explained by enzymes we find in the brain, suggesting they may originate from an external source such as the gut microbiome. These findings motivate further research into bile acid metabolism and transport in AD to elucidate their possible connection to cognitive decline. |
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| Keywords: |
Alzheimer's disease; bile acids; cholesterol metabolism; transcriptomics; metabolomics; genome-scale metabolic models; transcriptional regulatory networks |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
BBSRC |
| Issue: |
8 |
| Start Page: |
100138 |