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Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untarg...

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Autores principales: Dehghan, Abbas, Pinto, Rui Climaco, Karaman, Ibrahim, Huang, Jian, Durainayagam, Brenan R., Ghanbari, Mohsen, Nazeer, Areesha, Zhong, Qi, Liggi, Sonia, Whiley, Luke, Mustafa, Rima, Kivipelto, Miia, Solomon, Alina, Ngandu, Tiia, Kanekiyo, Takahisa, Aikawa, Tomonori, Radulescu, Carola I., Barnes, Samuel J., Graça, Gonçalo, Chekmeneva, Elena, Camuzeaux, Stephane, Lewis, Matthew R., Kaluarachchi, Manuja R., Ikram, M. Arfan, Holmes, Elaine, Tzoulaki, Ioanna, Matthews, Paul M., Griffin, Julian L., Elliott, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618092/
https://www.ncbi.nlm.nih.gov/pubmed/36269859
http://dx.doi.org/10.1073/pnas.2206083119
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author Dehghan, Abbas
Pinto, Rui Climaco
Karaman, Ibrahim
Huang, Jian
Durainayagam, Brenan R.
Ghanbari, Mohsen
Nazeer, Areesha
Zhong, Qi
Liggi, Sonia
Whiley, Luke
Mustafa, Rima
Kivipelto, Miia
Solomon, Alina
Ngandu, Tiia
Kanekiyo, Takahisa
Aikawa, Tomonori
Radulescu, Carola I.
Barnes, Samuel J.
Graça, Gonçalo
Chekmeneva, Elena
Camuzeaux, Stephane
Lewis, Matthew R.
Kaluarachchi, Manuja R.
Ikram, M. Arfan
Holmes, Elaine
Tzoulaki, Ioanna
Matthews, Paul M.
Griffin, Julian L.
Elliott, Paul
author_facet Dehghan, Abbas
Pinto, Rui Climaco
Karaman, Ibrahim
Huang, Jian
Durainayagam, Brenan R.
Ghanbari, Mohsen
Nazeer, Areesha
Zhong, Qi
Liggi, Sonia
Whiley, Luke
Mustafa, Rima
Kivipelto, Miia
Solomon, Alina
Ngandu, Tiia
Kanekiyo, Takahisa
Aikawa, Tomonori
Radulescu, Carola I.
Barnes, Samuel J.
Graça, Gonçalo
Chekmeneva, Elena
Camuzeaux, Stephane
Lewis, Matthew R.
Kaluarachchi, Manuja R.
Ikram, M. Arfan
Holmes, Elaine
Tzoulaki, Ioanna
Matthews, Paul M.
Griffin, Julian L.
Elliott, Paul
author_sort Dehghan, Abbas
collection PubMed
description Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10(−5) to 1.3 × 10(−44)). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049–1.4 × 10(−5)), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.
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spelling pubmed-96180922022-10-31 Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease Dehghan, Abbas Pinto, Rui Climaco Karaman, Ibrahim Huang, Jian Durainayagam, Brenan R. Ghanbari, Mohsen Nazeer, Areesha Zhong, Qi Liggi, Sonia Whiley, Luke Mustafa, Rima Kivipelto, Miia Solomon, Alina Ngandu, Tiia Kanekiyo, Takahisa Aikawa, Tomonori Radulescu, Carola I. Barnes, Samuel J. Graça, Gonçalo Chekmeneva, Elena Camuzeaux, Stephane Lewis, Matthew R. Kaluarachchi, Manuja R. Ikram, M. Arfan Holmes, Elaine Tzoulaki, Ioanna Matthews, Paul M. Griffin, Julian L. Elliott, Paul Proc Natl Acad Sci U S A Biological Sciences Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10(−5) to 1.3 × 10(−44)). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049–1.4 × 10(−5)), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD. National Academy of Sciences 2022-10-21 2022-10-25 /pmc/articles/PMC9618092/ /pubmed/36269859 http://dx.doi.org/10.1073/pnas.2206083119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Dehghan, Abbas
Pinto, Rui Climaco
Karaman, Ibrahim
Huang, Jian
Durainayagam, Brenan R.
Ghanbari, Mohsen
Nazeer, Areesha
Zhong, Qi
Liggi, Sonia
Whiley, Luke
Mustafa, Rima
Kivipelto, Miia
Solomon, Alina
Ngandu, Tiia
Kanekiyo, Takahisa
Aikawa, Tomonori
Radulescu, Carola I.
Barnes, Samuel J.
Graça, Gonçalo
Chekmeneva, Elena
Camuzeaux, Stephane
Lewis, Matthew R.
Kaluarachchi, Manuja R.
Ikram, M. Arfan
Holmes, Elaine
Tzoulaki, Ioanna
Matthews, Paul M.
Griffin, Julian L.
Elliott, Paul
Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease
title Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease
title_full Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease
title_fullStr Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease
title_full_unstemmed Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease
title_short Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease
title_sort metabolome-wide association study on abca7 indicates a role of ceramide metabolism in alzheimer’s disease
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618092/
https://www.ncbi.nlm.nih.gov/pubmed/36269859
http://dx.doi.org/10.1073/pnas.2206083119
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