Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer’s disease
Communications Biology, vol. 5, pp. 1074
Abstract
Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.
Authors 53
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Purdue University West Lafayette · Institute for Systems Biology
Affiliation as printed
Institute for Systems Biology, Seattle, WA, USA
School of Health Sciences, Purdue University, West Lafayette, IN, USA
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Duke University · Helmholtz Munich · Institute of Computational Biology
Affiliation as printed
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
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SUNY Downstate Health Sciences University
Affiliation as printed
Department of Neurology/Pharmacology, SUNY Downstate Medical Center, Brooklyn, NY, USA
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Indiana University Indianapolis · Indiana University School of Medicine · Indiana University – Purdue University Indianapolis
Affiliation as printed
Indiana Alzheimer's Disease Research Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
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SUNY Downstate Health Sciences University
Affiliation as printed
Department of Neurology/Pharmacology, SUNY Downstate Medical Center, Brooklyn, NY, USA
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Baker Heart and Diabetes Institute
Affiliation as printed
Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
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Helmholtz Munich · Institute of Computational Biology
Affiliation as printed
Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
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Affiliation as printed
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
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Weill Cornell Medical College in Qatar · Weill Cornell Medicine
Affiliation as printed
Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, PO 24144, Doha, Qatar
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Indiana University Indianapolis · Indiana University School of Medicine · Indiana University – Purdue University Indianapolis
Affiliation as printed
Indiana Alzheimer's Disease Research Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
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Affiliation as printed
Lipidomics Consulting Ltd., Esbo, Finland
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Baker Heart and Diabetes Institute
Affiliation as printed
Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
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Affiliation as printed
Institute for Systems Biology, Seattle, WA, USA
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Affiliation as printed
Institute for Systems Biology, Seattle, WA, USA
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Affiliation as printed
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
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Rima F Kaddurah-Daouk corresponding
Duke University · Duke Medical Center
Affiliation as printed
Department of Medicine, Duke University, Durham, NC, USA. kaddu001@mc.duke.edu
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA. kaddu001@mc.duke.edu
Duke Institute of Brain Sciences, Duke University, Durham, NC, USA. kaddu001@mc.duke.edu
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
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Affiliation as printed
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
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Affiliation as printed
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
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Affiliation as printed
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
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Affiliation as printed
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
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Affiliation as printed
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA
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Affiliation as printed
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA
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Indiana University Indianapolis · Indiana University School of Medicine · Indiana University – Purdue University Indianapolis
Affiliation as printed
Indiana Alzheimer’s Disease Research Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
Indiana Alzheimer's Disease Research Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
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Indiana University Indianapolis · Indiana University School of Medicine · Indiana University – Purdue University Indianapolis
Affiliation as printed
Indiana Alzheimer’s Disease Research Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
Indiana Alzheimer's Disease Research Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
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Baker Heart and Diabetes Institute
Affiliation as printed
Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
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Affiliation as printed
Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands
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Affiliation as printed
Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands
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Thomas Hankemeier Aachen Division of Analytical Biosciences Leiden/Amsterdam Center for Drug Research
Affiliation as printed
Division of Analytical Biosciences, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands
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SUNY Downstate Health Sciences University
Affiliation as printed
Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY, USA
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Ollscoil na Gaillimhe – University of Galway
Affiliation as printed
National University of, Ireland, Galway, Ireland
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Ollscoil na Gaillimhe – University of Galway
Affiliation as printed
National University of, Ireland, Galway, Ireland
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Ollscoil na Gaillimhe – University of Galway
Affiliation as printed
National University of, Ireland, Galway, Ireland
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Ollscoil na Gaillimhe – University of Galway
Affiliation as printed
National University of, Ireland, Galway, Ireland
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Ollscoil na Gaillimhe – University of Galway
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National University of, Ireland, Galway, Ireland
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Boston University, Boston, MA, USA
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Boston University, Boston, MA, USA
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Boston University, Boston, MA, USA
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Boston University, Boston, MA, USA
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University of Alberta, Edmonton, AB, Canada
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University of California, Davis
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University of California, Davis, CA, USA
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University of Hawaiʻi at Mānoa
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University of Hawaii-Manoa, Honolulu, HI, USA
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University of Hawaiʻi at Mānoa
Affiliation as printed
University of Hawaii-Manoa, Honolulu, HI, USA
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University of Hawaiʻi at Mānoa
Affiliation as printed
University of Hawaii-Manoa, Honolulu, HI, USA
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University of Hawaiʻi at Mānoa
Affiliation as printed
University of Hawaii-Manoa, Honolulu, HI, USA
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Affiliation as printed
University of Pennsylvania, Philadelphia, PA, USA
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Affiliation as printed
University of Pennsylvania, Philadelphia, PA, USA
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Affiliation as printed
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
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Affiliation as printed
Institute for Systems Biology, Seattle, WA, USA
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SUNY Downstate Health Sciences University
Affiliation as printed
Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY, USA
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Helmholtz Munich · Institute of Computational Biology
Affiliation as printed
Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Rosa & Co LLC, San Carlos, CA, USA
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Xianlin Han corresponding
The University of Texas at San Antonio Health Science Center
Affiliation as printed
University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. hanx@uthscsa.edu
University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Cited by 109 stored of 114
Cited by patents worldwide 1 (Lens.org)
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CERAMIDE AND SPHINGOMYELIN IN NEUROLOGICAL DISORDERSWO2022226427A3 2023-01-26 Pending