Biochemical identification of the neutral endopeptidase family member responsible for the catabolism of amyloid β 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-limiting proteolysis of A beta in vivo, but the exact molecular identity of the peptidase(s) has remained unknown because of the molecular redundancy of such activity. We analyzed the brain-derived enzyme by means of immune-depletion and gene disruption, and demonstrate here that neprilysin accounts for the majority of the A beta -degrading activity. Furthermore, kinetic analysis, giving a K-m value of 2.8 +/- 0.76 muM, indicated that A beta (1-42) is a relevant substrate for neprilysin.