학술논문
Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease
Document Type
Report
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.; Graca, Goncalo; 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
Source
Proceedings of the National Academy of Sciences of the United States. October 25, 2022, Vol. 119 Issue 43, p1v, 12 p.
Subject
Language
English
ISSN
0027-8424
Abstract
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.sup.-5] to 1.3 * [10.sup.-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.sup.-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 ABCA7is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD. genome-wide association study | Alzheimer's disease | ABCA7 | metabolomics | ceramide