| First Author | Hafez D | Year | 2011 |
| Journal | Am J Pathol | Volume | 178 |
| Issue | 1 | Pages | 306-12 |
| PubMed ID | 21224067 | Mgi Jnum | J:168082 |
| Mgi Id | MGI:4881858 | Doi | 10.1016/j.ajpath.2010.11.012 |
| Citation | Hafez D, et al. (2011) Neprilysin-2 is an important beta-amyloid degrading enzyme. Am J Pathol 178(1):306-12 |
| abstractText | Proteases that degrade the amyloid-beta peptide (Abeta) are important in protecting against Alzheimer's disease (AD), and understanding these proteases is critical to understanding AD pathology. Endopeptidases sensitive to inhibition by thiorphan and phosphoramidon are especially important, because these inhibitors induce dramatic Abeta accumulation ( approximately 30- to 50-fold) and pathological deposition in rodents. The Abeta-degrading enzyme neprilysin (NEP) is the best known target of these inhibitors. However, genetic ablation of NEP results in only modest increases ( approximately 1.5- to 2-fold) in Abeta, indicating that other thiorphan/phosphoramidon-sensitive endopeptidases are at work. Of particular interest is the NEP homolog neprilysin 2 (NEP2), which is thiorphan/phosphoramidon-sensitive and degrades Abeta. We investigated the role of NEP2 in Abeta degradation in vivo through the use of gene knockout and transgenic mice. Mice deficient for the NEP2 gene showed significant elevations in total Abeta species in the hippocampus and brainstem/diencephalon ( approximately 1.5-fold). Increases in Abeta accumulation were more dramatic in NEP2 knockout mice crossbred with APP transgenic mice. In NEP/NEP2 double-knockout mice, Abeta levels were marginally increased ( approximately 1.5- to 2-fold), compared with NEP(-/-)/NEP2(+/+) controls. Treatment of these double-knockout mice with phosphoramidon resulted in elevations of Abeta, suggesting that yet other NEP-like Abeta-degrading endopeptidases are contributing to Abeta catabolism. |
