Biochemical identification of the neutral endopeptidase family member responsible for the catabolism of amyloid beta peptide in the brain

Amyloid beta peptide (A beta) is a physiological peptide that is constantly catabolized in the brain. We previously demonstrated that an endopeptidase sensitive to phosphoramidon and thiorphan conducts the initial rate-limiti ng proteolysis of A beta in vivo, but the exact molecular identity of the p eptidase(s) has remained unknown because of the molecular redundancy of suc h activity. We analyzed the brain-derived enzyme by means of immune-depleti on and gene disruption, and demonstrate here that neprilysin accounts for t he majority of the A beta -degrading activity. Furthermore, kinetic analysi s, giving a K-m value of 2.8 +/- 0.76 muM, indicated that A beta (1-42) is a relevant substrate for neprilysin.