Bibliographic Details
| Title: |
Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease. |
| Authors: |
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. |
| Source: |
Molecular Psychiatry. Dec2004, Vol. 9 Issue 12, p1122-1128. 7p. |
| Subjects: |
Enzymes, Endothelins, Enzymology, Alzheimer's disease, Psychiatry, Behavioral medicine |
| Abstract: |
Cerebral accumulation ofß-amyloid peptide (Aß) is a central event in the pathogenesis of Alzheimer's disease (AD). Endothelin-converting enzyme-1 (ECE-1) is a candidate Aß-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 Aßdeposition, further suggesting a physiological role in Aßclearance. 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 Aßclearance and offer new potential targets for therapeutic interventions in AD.Molecular Psychiatry (2004) 9, 1122-1128. doi:10.1038/sj.mp.4001584 Published online 31 August 2004 [ABSTRACT FROM AUTHOR] |
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| Database: |
Psychology and Behavioral Sciences Collection |
