The −980C /G polymorphism in APH‐1A promoter confers risk of Alzheimer’s disease

Summary We previously described an association between Alzheimer’s disease (AD) and a single‐nucleotide polymorphism −980C/G (rs3754048) in the promoter of the anterior pharynx‐defective‐1a ( APH‐1A ) gene. Here, we examine the potential of this −980C/G polymorphism to affect APH‐1A transcription and confer a risk of AD. We validated the presence of APH‐1A promoter polymorphism −980C/G in other two Chinese cohort sets (450 AD and 450 controls). Subsequently, we measured APH‐1A mRNA and protein levels and γ‐secretase activity in C or G allele carriers. Finally, we examined the polymorphism’s transcriptional function using a dual‐luciferase reporter assay and also tracked transcription factor binding to the variant promoter sequence with electrophoretic mobility shift assays (EMSAs). We found that the APH‐1A levels and γ‐secretase activity were higher in individuals carrying allele G. The G allele increased APH‐1A transcriptional activity significantly in both N2A cells and HEK293 cells. The EMSA revealed an increased binding of the transcription factor Yin Yang 1 (YY1) to allele G. Overexpression of YY1 resulted in an activation of the APH‐1A promoter (2.7‐fold). Specific YY1 siRNA led to decreases in APH‐1A promoter activity and mRNA and protein levels. Our data indicate that the APH‐1A promoter polymorphism −980C/G might alter the binding ability of YY1 transcription factor, resulting in an increased level of APH‐1A and γ‐secretase activity. These factors further facilitated β‐amyloid (Aβ) 42 generation and ultimately modified patients’ susceptibility to AD. The involvement of transcription factor YY1 might be a novel mechanism for the development of AD.