title: Promoter polymorphisms which modulate APP expression may increase susceptibility to Alzheimer's disease.
abstract: Increasing evidence indicates that variants in promoter of the beta-amyloid precursor protein (APP) gene could up-regulate the APP gene expression and aggravate the amyloid beta protein (A beta) accumulation, thus contributing to the development of Alzheimer's disease (AD). In Chinese Han populations we found three polymorphisms in APP promoter: -877T/C(rs466433), -955A/G(rs364048) and -9G/C. The -877T and -955A alleles were over-represented in 209 sporadic AD (SAD) patients when compared to those in 437 healthy individuals. Furthermore, -877T/C and -955A/G were in strong linkage disequilibrium and they constructed a relatively risky -877T/-955A and a relatively protective -877C/-955G. Luciferase reporter assay indicated -877T/-955A had four times higher transcriptional activity than -877C/-955G. A more marked increase in -877T/-955A transcriptional activity was seen when under A beta(25-35) treatment. As for the -9G/C polymorphism, significant differences between the two alleles were not observed either in genetic evaluation or in functional assay. The present study provides strong evidence that APP promoter polymorphisms that significantly increase APP expression levels are associated with development of SAD.
authors.affiliation: Department of Neurology, Xuanwu Hospital of the Capital University of Medical Sciences, Beijing 100053, PR China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Lv
authors.forename: Longfei
authors.initials: L
authors.lastname: Jia
authors.forename: Jianping
authors.initials: J
authors.lastname: Jia
mesh_terms: D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004198:Disease Susceptibility; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005787:Gene Frequency; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013431:Sulfates / Q000494:pharmacology; D014162:Transfection / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D013431:Sulfates; C074636:amyloid beta-protein (25-35); C012036:sodium sulfate; D006861:Hydrogen Peroxide