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.