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

The amyloid beta (A beta) 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 beta cleaves APP and liberates soluble N-terminal APP (N-APP) fragments. In this work, we present evidence that meprin beta can also process APP in a manner reminiscent of beta-secretase. We identified cleavage sites of meprin beta in the amyloid beta sequence of the wild type and Swedish mutant of APP at positions p1 and p2, thereby generating A beta variants starting at the first or second amino acid residue. We observed even higher kinetic values for meprin beta than BACE1 for both the wild type and the Swedish mutant APP form. This enzymatic activity of meprin beta on APP and A beta generation was also observed in the absence of BACE1/2 activity using a beta-secretase inhibitor and BACE knock-out cells, indicating that meprin beta acts independently of beta-secretase.