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BibTex format

@article{Dehghan:2022:10.1073/pnas.2206083119,
author = {Dehghan, A and Pinto, RC and Karaman, I and Huang, J and Durainayagam, BR and Ghanbari, M and Nazeer, A and Zhong, Q and Liggi, S and Whiley, L and Mustafa, R and Kivipelto, M and Solomon, A and Ngandu, T and Kanekiyo, T and Aikawa, T and Radulescu, CI and Barnes, SJ and Graça, G and Chekmeneva, E and Camuzeaux, S and Lewis, MR and Kaluarachchi, MR and Ikram, MA and Holmes, E and Tzoulaki, I and Matthews, PM and Griffin, JL and Elliott, P},
doi = {10.1073/pnas.2206083119},
journal = {Proceedings of the National Academy of Sciences of USA},
pages = {1--12},
title = {Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease.},
url = {http://dx.doi.org/10.1073/pnas.2206083119},
volume = {119},
year = {2022}
}

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TY  - JOUR
AB  - 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.
AU  - Dehghan,A
AU  - Pinto,RC
AU  - Karaman,I
AU  - Huang,J
AU  - Durainayagam,BR
AU  - Ghanbari,M
AU  - Nazeer,A
AU  - Zhong,Q
AU  - Liggi,S
AU  - Whiley,L
AU  - Mustafa,R
AU  - Kivipelto,M
AU  - Solomon,A
AU  - Ngandu,T
AU  - Kanekiyo,T
AU  - Aikawa,T
AU  - Radulescu,CI
AU  - Barnes,SJ
AU  - Graça,G
AU  - Chekmeneva,E
AU  - Camuzeaux,S
AU  - Lewis,MR
AU  - Kaluarachchi,MR
AU  - Ikram,MA
AU  - Holmes,E
AU  - Tzoulaki,I
AU  - Matthews,PM
AU  - Griffin,JL
AU  - Elliott,P
DO  - 10.1073/pnas.2206083119
EP  - 12
PY  - 2022///
SN  - 0027-8424
SP  - 1
TI  - Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease.
T2  - Proceedings of the National Academy of Sciences of USA
UR  - http://dx.doi.org/10.1073/pnas.2206083119
UR  - https://www.ncbi.nlm.nih.gov/pubmed/36269859
UR  - https://www.pnas.org/doi/10.1073/pnas.2206083119
UR  - http://hdl.handle.net/10044/1/100823
VL  - 119
ER  -

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Professor Paul M. Matthews

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