Proceedings of the National Academy of Sciences of the United States of America · 2022
Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease.
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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
Аннотация
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.