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

Priyanka Baloni, Cory C. Funk, Jingwen Yan, James T. Yurkovich, Alexandra Kueider-Paisley, Kwangsik Nho, Almut Heinken, Wei Jia, Siamak Mahmoudiandehkordi, Gregory Louie, Andrew J. Saykin, Matthias Arnold, Gabi Kastenmüller, William Griffiths Orcid Logo, 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 Orcid Logo

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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...

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Published in: Cell Reports Medicine
ISSN: 2666-3791
Published: Elsevier BV 2020
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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. 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spelling 2021-11-26T08:57:47.9077393 v2 55544 2020-10-28 Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false 2020-10-28 BMS 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. Journal Article Cell Reports Medicine 1 8 100138 Elsevier BV 2666-3791 Alzheimer&apos;s disease; bile acids; cholesterol metabolism; transcriptomics; metabolomics; genome-scale metabolic models; transcriptional regulatory networks 17 11 2020 2020-11-17 10.1016/j.xcrm.2020.100138 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University BBSRC BB/I001735/1, BB/N015932/1 2021-11-26T08:57:47.9077393 2020-10-28T17:41:35.4526260 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Priyanka Baloni 1 Cory C. Funk 2 Jingwen Yan 3 James T. Yurkovich 4 Alexandra Kueider-Paisley 5 Kwangsik Nho 6 Almut Heinken 7 Wei Jia 8 Siamak Mahmoudiandehkordi 9 Gregory Louie 10 Andrew J. Saykin 11 Matthias Arnold 12 Gabi Kastenmüller 13 William Griffiths 0000-0002-4129-6616 14 Ines Thiele 15 Rima Kaddurah-Daouk 16 Nathan D. Price 17 Rima Kaddurah-Daouk 18 Alexandra Kueider-Paisley 19 Gregory Louie 20 P. Murali Doraiswamy 21 Colette Blach 22 Arthur Moseley 23 J. Will Thompson 24 Siamak Mahmoudiandehkhordi 25 Kathleen Welsh-Balmer 26 Brenda Plassman 27 Andrew Saykin 28 Kwangsik Nho 29 Gabi Kastenmüller 30 Matthias Arnold 31 Sudeepa Bhattacharyya 32 Xianlin Han 33 Rebecca Baillie 34 Oliver Fiehn 35 Dinesh Barupal 36 Peter Meikle 37 Sarkis Mazmanian 38 Mitchel Kling 39 Leslie Shaw 40 John Trojanowski 41 Jon Toledo 42 Cornelia van Duijin 43 Thomas Hankemier 44 Ines Thiele 45 Almut Heinken 46 Nathan Price 47 Cory Funk 48 Priyanka Baloni 49 Wei Jia 50 David Wishart 51 Roberta Brinton 52 Rui Chang 53 Lindsay Farrer 54 Rhoda Au 55 Wendy Qiu 56 Peter Würtz 57 Lara Mangravite 58 Jan Krumsiek 59 John Newman 60 Bin Zhang 61 Herman Moreno 62 55544__18526__a8ab25f1f332428594327cdb13c891eb.pdf 200611_Baloni-Cell Reports Medicine-Paper_revised-final (2).docx 2020-10-29T08:52:48.6816207 Output 2402376 application/vnd.openxmlformats-officedocument.wordprocessingml.document Author's Original true false 55544__18682__e847cba5b9cd4fe7bf247020a68b8c04.pdf mmc15.pdf 2020-11-18T08:49:45.4961674 Output 4236328 application/pdf Version of Record true ©2020 The Authors. This is an open access article under the CC BY-NC-ND license true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
spellingShingle Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
William Griffiths
title_short Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
title_full Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
title_fullStr Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
title_full_unstemmed Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
title_sort Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
author_id_str_mv 3316b1d1b524be1831790933eed1c26e
author_id_fullname_str_mv 3316b1d1b524be1831790933eed1c26e_***_William Griffiths
author William Griffiths
author2 Priyanka Baloni
Cory C. Funk
Jingwen Yan
James T. Yurkovich
Alexandra Kueider-Paisley
Kwangsik Nho
Almut Heinken
Wei Jia
Siamak Mahmoudiandehkordi
Gregory Louie
Andrew J. Saykin
Matthias Arnold
Gabi Kastenmüller
William Griffiths
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
format Journal article
container_title Cell Reports Medicine
container_volume 1
container_issue 8
container_start_page 100138
publishDate 2020
institution Swansea University
issn 2666-3791
doi_str_mv 10.1016/j.xcrm.2020.100138
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description 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.
published_date 2020-11-17T04:09:50Z
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score 11.036706

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