DNA polymorphism in the human presenilin‐2 promoter: altered gene activity and potential contribution to the risk for AD

Abstract

We analyzed the presenilin‐2 (PS2) promoter for polymorphisms in Alzheimer's disease (AD). Multiple elements responsive to pro‐inflammatory (PI) and hypoxia signalling were identified. In cultured human brain cells these factors induced the expression of the endogenous PS2 gene. DNA sequence analysis revealed an adenine (A) nucleotide deletion in the PS2 promoter in several human populations. Examination of cohorts of AD patients revealed no significant differences in the frequency of this polymorphism, however, regression analysis of polymorphic allele frequency suggested an association (p = 0.012) of the –A/–A mutant genotype with an increased risk of AD in apoE4 noncarriers and a tendency for an association with early onset AD. Gel shift assay showed that this mutation negates binding of interferon IRF2 repressor in nuclear extracts from aged human brain while creating a C/EBPβ regulatory element responsive to PI induction. Reporter assay in PS2 mutant promoter‐transfected human neural cells shows that mutant PS2 exhibits a 1.8‐fold higher level of basal expression that is synergistically induced 3.2‐fold over wild‐type PS2 by [IL‐1β + Aβ42]. These results suggest that under PI and oxygen stress conditions this PS2 promoter polymorphism enhances PS2 expression and may play a role in the induction and/or proliferation of a PI response in aging and in AD brain.