Genetic variations in ABCA7 can increase secreted levels of amyloid-β40 and amyloid-β42 peptides and ABCA7 transcription in cell culture models

From National Research Council Canada

DOIResolve DOI: https://doi.org/10.3233/JAD-150965
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Name affiliation
  1. National Research Council Canada. Human Health Therapeutics
FormatText
TypeArticle
Journal titleJournal of Alzheimer's Disease
ISSN13872877
18758908
Volume53
Issue3
Pages875–892
SubjectABC transporters; ABCA7 protein; Alzheimer’s disease; amyloid beta-peptides; BACE1 protein; genome-wide association study; myristoylation; SNPs
Abstract
Alzheimer’s disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.Gly1527Ala), are significantly associated with LOAD risk; however, the mechanism of this association is unknown. Functional consequences of both SNPs were examined in HEK293 and CHO cells stably expressing AβPP Swe. Luciferase reporter assays in HEK293 cells suggested that intron13 carrying rs3764650 major T-allele (int13-T) possessed promoter-enhancing capabilities. Co-transfection experiments with hABCA7 and int13-T resulted in significantly increased ABCA7 protein level relative to that with int13-G. Expression of hABCA7 carrying rs3752246 risk allele led to increases in secreted Aβ 40 and Aβ 42 and β-secretase activity in CHO- and HEK-AβPP Swe cells. Hydroxymyristic acid treatment of cells expressing hABCA7 carrying the rs3752246 major G allele resulted in increased β-secretase activity and levels of Aβ, suggesting that lack of myristoylation contributes to the observed cell-phenotypes. Molecular weight determination, by gel-electrophoresis and mass spectrometry, of hABCA7 peptides spanning position 1527 showed loss of post-translational modification in the risk-allele peptide. These results suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology.
Publication date
PublisherIOS Press
NoteErratum published in vol. 66, no. 2, pp. 853-854, 2018. DOI: 10.3233/JAD-189009
LanguageEnglish
Peer reviewedYes
NPARC number23000686
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