TY - JOUR
T1 - Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease
AU - Dehghan, Abbas
AU - Pinto, Rui Climaco
AU - Karaman, Ibrahim
AU - Huang, Jian
AU - Durainayagam, Brenan R.
AU - Ghanbari, Mohsen
AU - Nazeer, Areesha
AU - Zhong, Qi
AU - Liggi, Sonia
AU - Whiley, Luke
AU - Mustafa, Rima
AU - Kivipelto, Miia
AU - Solomon, Alina
AU - Ngandu, Tiia
AU - Kanekiyo, Takahisa
AU - Aikawa, Tomonori
AU - Radulescu, Carola I.
AU - Barnes, Samuel J.
AU - Graça, Gonçalo
AU - Chekmeneva, Elena
AU - Camuzeaux, Stephane
AU - Lewis, Matthew R.
AU - Kaluarachchi, Manuja R.
AU - Ikram, M. Arfan
AU - Holmes, Elaine
AU - Tzoulaki, Ioanna
AU - Matthews, Paul M.
AU - Griffin, Julian L.
AU - Elliott, Paul
N1 - Publisher Copyright:
Copyright © 2022 the Author(s). Published by PNAS.
PY - 2022/10/21
Y1 - 2022/10/21
N2 - 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.
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.
UR - https://www.scopus.com/pages/publications/85140348906
U2 - 10.1073/pnas.2206083119
DO - 10.1073/pnas.2206083119
M3 - Article
C2 - 36269859
AN - SCOPUS:85140348906
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 43
M1 - e2206083119
ER -