title: The -980C/G polymorphism in APH-1A promoter confers risk of Alzheimer's disease.
abstract: 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.
authors: 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.
authors: Wei
authors: W
authors: Qin
authors: Longfei
authors: L
authors: Jia
authors: Aihong
authors: A
authors: Zhou
authors: Xiumei
authors: X
authors: Zuo
authors: Zhe
authors: Z
authors: Cheng
authors: Fen
authors: F
authors: Wang
authors: Fudong
authors: F
authors: Shi
authors: Jianping
authors: J
authors: Jia
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D010450:Endopeptidases; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012306:Risk; D012307:Risk Factors; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C475154:APH1A protein, human; D010450:Endopeptidases; D010447:Peptide Hydrolases