Biochemical Identification of the Neutral Endopeptidase Family Member Responsible for the Catabolism of Amyloid β Peptide in the Brain

Abstract

Amyloid β peptide (Aβ) 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 Aβ 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 inununo-depletion and gene disruption, and demonstrate here that neprilysin accounts for the majority of the Aβ-degrading activity. Furthermore, kinetic analysis, giving a K_m value of 2.8±0.76 μM, indicated that Aβ_1-42 is a relevant substrate for neprilysin.