Abstract
The insulin degrading enzyme (IDE) variant, v311 (rs6583817), is associated with increased post-mortem cerebellar IDE mRNA, decreased plasma β-amyloid (Aβ), decreased risk for Alzheimer's disease (AD) and increased reporter gene expression, suggesting that it is a functional variant driving increased IDE expression. To identify other functional IDE variants, we have tested v685, rs11187061 (associated with decreased cerebellar IDE mRNA) and variants on H6, the haplotype tagged by v311 (v10; rs4646958, v315; rs7895832, v687; rs17107734 and v154; rs4646957), for altered in vitro reporter gene expression. The reporter gene expression levels associated with the second most common haplotype (H2) successfully replicated the post-mortem findings in hepatocytoma (0.89 fold-change, p = 0.04) but not neuroblastoma cells. Successful in vitro replication was achieved for H6 in neuroblastoma cells when the sequence was cloned 5′ to the promoter (1.18 fold-change, p = 0.006) and 3′ to the reporter gene (1.29 fold change, p = 0.003), an effect contributed to by four variants (v10, v315, v154 and v311). Since IDE mediates Aβ degradation, variants that regulate IDE expression could represent good therapeutic targets for AD.
Highlights
Aggregated b-amyloid (Ab) is a pathological hallmark of the Alzheimer’s Disease (AD) brain
Since rs6583817 (v311), a variant present on both H6 and H9, was individually associated with an increase in the level of Insulin degrading enzyme (IDE) transcript, increased in vitro reporter gene expression and decreased risk of late-onset AD (LOAD), we proposed a simple model in which v311 is the functional variant that influences IDE expression and LOAD risk
All the variants tested here are either intronic or lie in the 39 flanking region. Since none of these variants lie within 1.5 kb of a promoter region, all variants were tested for enhancer rather than promoter activity
Summary
Aggregated b-amyloid (Ab) is a pathological hallmark of the Alzheimer’s Disease (AD) brain. Farris et al reported that IDE knock-out mice presented with a .50% decrease in Ab degradation in both brain membrane fractions and primary neuronal cultures and increased cerebral accumulation of endogenous Ab [8]. It follows that disturbed IDE expression and/or activity could contribute to amyloid fibril formation [9]. The gene encoding IDE (IDE), located on chromosome 10q23.33, represents a strong AD candidate gene because of its location near a ‘‘suggestive’’ linkage peak (10q24) found in two genome-wide linkage studies of late-onset AD (LOAD) families [10,11] and a ‘‘significant’’ linkage peak (10q) in a third [12]. Several studies have reported significant association of IDE haplotypes with LOAD [13,14,15], as well as with plasma Ab42 levels in extended LOAD families [14], with plaque density [13] and cognitive function [14]
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