Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions
Year: 2019
Type: preprint
Study design: Observational Study
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 alternative bile acid synthesis pathway was expressed in 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.
DOI: 10.1101/782987
Authors: 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 J Griffiths, Ines Thiele, Rima Kaddurah-Daouk, Nathan D. Price
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Swansea University, Fonds National de la Recherche Luxembourg, National Institutes of Health, Directorate for Biological Sciences, Qatar National Research Fund, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, National Institute on Aging, U.S. National Library of Medicine
Awards: Epidemiologic Study of Neural Reserve and Neurobiology of Aging, G1171648585, Indiana Alzheimer Disease Center, G171247251, G3400019033, Gut Liver Brain Biochemical Axis in Alzheimer's Disease, Pathway discovery, validation and compound identification for Alzheimer's disease, G3912568052, G4669903861, G4874749982, Risk Factors, Pathology, and Clinical Expressions of AD, Rush Alzheimer's Disease Core Center, G5090083847, G5293636047, G5691375693, G5692282101, Integrating Neuroimaging, Multi-omics, and Clinical Data in Complex Disease, G710916345, G7268688694, Memory Circuitry in MCI and Early Alzheimerâs Disease Prodrome: Molecular Drivers, Metabolic Networks and Pathways in Alzheimer's Disease, Neurogenesis in Adult Brain: Gene Networks and Alzheimer’s Disease
OpenAlex ID: W2976657501