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

Aging Cell

Wei Qin²  Longfei Jia²  Aihong Zhou²  Xiumei Zuo²  Zhe Cheng²  Fen Wang²  Fudong Shi¹ 

[1] Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA;Department of Neurology, Xuan Wu Hospital of the Capital Medical University, and Neurodegenerative Laboratory of Ministry of Education of the People’s Republic of China, Beijing, China

关键词: Alzheimer’s disease;    APH‐1A gene;    polymorphism;    Yin Yang 1;    gene expression;    γ‐secretase;   

DOI  :  10.1111/j.1474-9726.2011.00708.x

来源: Wiley

【 摘 要 】

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.

【 授权许可】

Unknown   
© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland