The Metalloprotease Meprin β Generates Amino Terminal-truncated Amyloid β Peptide Species

Christoph Becker-Pauly,Lisa Munter,Tamara Jefferson,Claus U. Pietrzik,Gerd Multhaup,Thorsten Jumpertz,Jessica Bien,Mirsada Čaušević,Sascha Weggen

doi:10.1074/jbc.m112.395608

Abstract

The amyloid β (Aβ) peptide, which is abundantly found in the brains of patients suffering from Alzheimer disease, is central in the pathogenesis of this disease. Therefore, to understand the processing of the amyloid precursor protein (APP) is of critical importance. Recently, we demonstrated that the metalloprotease meprin β cleaves APP and liberates soluble N-terminal APP (N-APP) fragments. In this work, we present evidence that meprin β can also process APP in a manner reminiscent of β-secretase. We identified cleavage sites of meprin β in the amyloid β sequence of the wild type and Swedish mutant of APP at positions p1 and p2, thereby generating Aβ variants starting at the first or second amino acid residue. We observed even higher kinetic values for meprin β than BACE1 for both the wild type and the Swedish mutant APP form. This enzymatic activity of meprin β on APP and Aβ generation was also observed in the absence of BACE1/2 activity using a β-secretase inhibitor and BACE knock-out cells, indicating that meprin β acts independently of β-secretase.

Highlights

BackgroundResults: Meprin ␤-mediated cleavage of the amyloid precursor protein leads to an increase of amyloid ␤ production and to the generation of an N-terminal truncated amyloid ␤ variant
Meprin ␤ cleaves the amyloid precursor protein
Kinetics of A␤ Generation by Meprin ␤—We have recently demonstrated that the N-terminal extracellular domain of amyloid precursor protein (APP) is a substrate for the metalloproteinase meprin ␤

Summary

Background

Results: Meprin ␤-mediated cleavage of the amyloid precursor protein leads to an increase of amyloid ␤ production and to the generation of an N-terminal truncated amyloid ␤ variant. We identified cleavage sites of meprin ␤ in the amyloid ␤ sequence of the wild type and Swedish mutant of APP at positions p1 and p2, thereby generating A␤ variants starting at the first or second amino acid residue. We observed even higher kinetic values for meprin ␤ than BACE1 for both the wild type and the Swedish mutant APP form. We have recently shown that APP is processed by the metalloprotease meprin ␤, generating novel, soluble N-terminal APP fragments [15]. Our results demonstrate that meprin ␤ processes APP by generating truncated A␤ peptides starting in p2 position independent of BACE1

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION