Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease.

Autor: Baloni P; Institute for Systems Biology, Seattle, WA, USA.; School of Health Sciences, Purdue University, West Lafayette, IN, USA., Arnold M; Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA., Buitrago L; Department of Neurology/Pharmacology, SUNY Downstate Medical Center, Brooklyn, NY, USA., Nho K; Indiana Alzheimer's Disease Research Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA., Moreno H; Department of Neurology/Pharmacology, SUNY Downstate Medical Center, Brooklyn, NY, USA., Huynh K; Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia., Brauner B; Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany., Louie G; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA., Kueider-Paisley A; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA., Suhre K; Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, PO 24144, Doha, Qatar., Saykin AJ; Indiana Alzheimer's Disease Research Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA., Ekroos K; Lipidomics Consulting Ltd., Esbo, Finland., Meikle PJ; Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia., Hood L; Institute for Systems Biology, Seattle, WA, USA., Price ND; Institute for Systems Biology, Seattle, WA, USA., Doraiswamy PM; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA., Funk CC; Institute for Systems Biology, Seattle, WA, USA., Hernández AI; Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY, USA., Kastenmüller G; Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany., Baillie R; Rosa & Co LLC, San Carlos, CA, USA., Han X; University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. hanx@uthscsa.edu., Kaddurah-Daouk R; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA. kaddu001@mc.duke.edu.; Department of Medicine, Duke University, Durham, NC, USA. kaddu001@mc.duke.edu.; Duke Institute of Brain Sciences, Duke University, Durham, NC, USA. kaddu001@mc.duke.edu.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2022 Oct 08; Vol. 5 (1), pp. 1074. Date of Electronic Publication: 2022 Oct 08.
DOI: 10.1038/s42003-022-04011-6
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje