Funalot B, Ouimet T, Claperon A, Fallet C, Delacourte A, Epelbaum J, Subkowski T, Léonard N, Codron V, David J-P, Amouyel P, Schwartz J-C, Helbecque N
Institut National de la Santé et de la Recherche Médicale Unit 573, 75014 Paris, France.
Mol Psychiatry. 2004 Dec;9(12):1122-8, 1059. doi: 10.1038/sj.mp.4001584.
Cerebral accumulation of beta-amyloid peptide (A beta) is a central event in the pathogenesis of Alzheimer's disease (AD). Endothelin-converting enzyme-1 (ECE-1) is a candidate A beta-degrading enzyme in brain, but its involvement in AD pathogenesis was never assessed. We first performed brain immunocytochemistry, using a monoclonal anti-ECE-1 antibody, and observed neuronal ECE-1 expression in various cortical regions of nondemented subjects. In the hippocampus, ECE-1 immunoreactivity showed a stereotypical pattern inversely correlated with susceptibility to A beta deposition, further suggesting a physiological role in A beta clearance. In order to undertake a genetic association study, we identified a functional genetic variant (ECE1B C-338A) located in a regulatory region of the ECE1 gene. We showed that the A allele is associated with increased transcriptional activity in promoter-reporter gene assays and with increased ECE-1 mRNA expression in human neocortex. In a case-control study involving 401 patients with late-onset AD and 461 aged controls, we found that homozygous carriers of the A allele had a reduced risk of AD (OR=0.47, 95% CI 0.25-0.88). This finding was strengthened by the analysis of two other genetic variants of the ECE1 gene, which showed that the genetic association is extended over at least 13 kilobases of the gene sequence. Our results suggest that ECE-1 expression in brain may be critical for cortical A beta clearance and offer new potential targets for therapeutic interventions in AD.
β-淀粉样肽（Aβ）在大脑中的蓄积是阿尔茨海默病（AD）发病机制中的核心事件。内皮素转化酶-1（ECE-1）是大脑中一种潜在的Aβ降解酶，但从未评估过其在AD发病机制中的作用。我们首先使用单克隆抗ECE-1抗体进行脑免疫细胞化学检测，观察到在非痴呆受试者的各个皮质区域有神经元ECE-1表达。在海马体中，ECE-1免疫反应性呈现出一种典型模式，与Aβ沉积易感性呈负相关，进一步表明其在Aβ清除中的生理作用。为了进行基因关联研究，我们在ECE1基因的调控区域鉴定出一个功能性基因变体（ECE1B C-338A）。我们发现在启动子-报告基因检测中，A等位基因与转录活性增加相关，并且在人类新皮质中与ECE-1 mRNA表达增加相关。在一项涉及401例晚发性AD患者和461例老年对照的病例对照研究中，我们发现A等位基因的纯合携带者患AD的风险降低（比值比=0.47，95%置信区间0.25-0.88）。对ECE1基因的另外两个基因变体的分析强化了这一发现，表明这种基因关联至少延伸到该基因序列的13千碱基。我们的结果表明，大脑中ECE-1的表达可能对皮质Aβ清除至关重要，并为AD的治疗干预提供了新的潜在靶点。
