Analysis of the nicastrin promoter rs10752637 polymorphism and its association with Alzheimer's disease.
Alzheimer's disease (AD) is a common, degenerative form of dementia characterized by the accumulation of plaques containing amyloid beta-peptides (A beta). Nicastrin (NCSTN) is a type I trans-membrane glycoprotein and an essential component of gamma-secretase, a multiprotein complex required for the production of the mature form of A beta. Overexpression of wild-type NCSTN increases A beta production, indicating that the strict regulation of NCSTN expression may play a fundamental role in the pathogenesis of AD. In this study we investigated the effect of a single-nucleotide polymorphism (SNP; rs10752637), located in the promoter region of the NCSTN gene, on NCSTN promoter activity. First, the rs10752637 genotypes were determined in a Chinese population consisting of 462 patients with sporadic AD and 470 normal control subjects. The distributions of the rs10752637 genotypes and allele frequencies were significantly different between the AD and control groups, with the -922T allele significantly associated with the occurrence of AD. Reporter assays indicated that the rs10752637 -922T allele had a significantly increased promoter activity relative to the -922G allele. Furthermore, gel shift assays demonstrated that the -922T allele preferentially bound to components of nuclear extracts. Overall, our results indicate that the rs10752637 SNP can likely influence the expression of NCSTN, and that this may be an influencing factor during the pathogenesis of AD.
Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. HL656@yahoo.com.cn
Li
L
Zhong
Qiu
Q
Dong-hai
Liu
L
Hong-ying
Lei
L
Qing-feng
D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
D008562:Membrane Glycoproteins; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases