Promoter polymorphisms which regulate ADAM9 transcription are protective against sporadic Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the formation of amyloid beta-peptides (Aβ peptides) and their deposition in the brain. A disintegrin and metalloproteinase (ADAM) 9 can cleave the amyloid precursor protein (APP) within the Aβ domain and preclude generation of Aβ peptides. We systematically screened ADAM9 gene promoter region and found four polymorphisms: -542C/T (rs10105311), -600A/C (rs7840270), -963A/G (rs6991968) and -1314T/C (rs7006414). The -1314C allele was over-represented in 345 healthy individuals when compared to that in 473 sporadic AD (SAD) patients (P=0.005) and constructed a relatively protective haplotype -542C/-600A/-963G/-1314C (OR=0.422, 95% CI 0.229-0.779). Luciferase reporter assay indicated that both -963G/-1314C and -963A/-1314C had higher transcriptional activity (1.5- to 1.8-fold and 1.4- to 1.7-fold respectively) than -963A/-1314T. Electrophoretic mobility shift assay (EMSA) revealed that the -1314C allele bound nuclear factors more strongly than the -1314T allele. Additionally, increased ADAM9 transcriptional activity was seen under estrogen treatment. Our data suggest that promoter polymorphisms which regulate ADAM9 transcription are protective against SAD.
Cong
Lin
L
Department of Neurology, Xuan Wu Hospital of Capital Medical University, Beijing 100053, PR China.
Jia
Jianping
J
D051722:ADAM Proteins / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D045744:Cell Line, Tumor; D016009:Chi-Square Distribution; D013196:Dihydrotestosterone / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014162:Transfection / Q000379:methods
D004967:Estrogens; D008565:Membrane Proteins; D013196:Dihydrotestosterone; D004958:Estradiol; D051722:ADAM Proteins; C098339:ADAM9 protein, human