|DOI||Resolve DOI: https://doi.org/10.3233/JAD-150965|
|Author||Search for: Bamji-Mirza, Michelle1; Search for: Li, Yan1; Search for: Najem, Dema1; Search for: Liu, Qing Yan1; Search for: Walker, Douglas; Search for: Lue, Lih-Fen; Search for: Stupak, Jacek1; Search for: Chan, Kenneth1; Search for: Li, Jianjun1; Search for: Ghani, Mahdi; Search for: Yang, Ze; Search for: Rogaeva, Ekaterina; Search for: Zhang, Wandong1|
- National Research Council of Canada. Human Health Therapeutics
|Subject||ABC transporters; ABCA7 protein; Alzheimer’s disease; amyloid beta-peptides; BACE1 protein; genome-wide association study; myristoylation; SNPs|
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.
|Note||Erratum published in vol. 66, no. 2, pp. 853-854, 2018. DOI: 10.3233/JAD-189009|
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