Neprilysin-2 Is an Important beta-Amyloid Degrading Enzyme

Proteases that degrade the amyloid-p peptide (A beta) 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 A beta accumulation (similar to 30- to 50-fold) and pathological deposition in rodents. The A beta-degrading enzyme neprilysin (NEP) is the best known target of these inhibitors. However, genetic ablation of NEP results in only modest increases (similar to 1.5- to 2-fold) in A beta, 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 A. We investigated the role of NEP2 in A beta degradation in vivo through the use of gene knockout and transgenic mice. Mice deficient for the NEP2 gene showed significant elevations in total A beta species in the hippocampus and brainstem/diencephalon (similar to 1.5-fold). Increases in A beta accumulation were more dramatic in NEP2 knockout mice crossbred with APP transgenic mice. In NEP/NEP2 double-knockout mice, A beta levels were marginally increased (similar to 1.5- to 2-fold), compared with NEP-/-/NEP2(+/+) controls. Treatment of these double-knockout mice with phosphoramidon resulted in elevations of A beta, suggesting that yet other NEP-like A beta-degrading endopeptidases are contributing to A beta catabolism. (Am Pathol 2011, 178:306-312; DOI: 10.1016/j.ajpath.2010.11.012)