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O2‐04‐04: The metalloprotease meprin beta generates amino‐terminally truncated beta‐amyloid peptide species
Author(s) -
Bien Jessica,
Jefferson Tamara,
Causevic Mirsada,
Jumpertz Thorsten,
Munter Lisa M.,
Multhaup Gerd,
Weggen Sascha,
BeckerPauly Christoph,
Pietrzik Claus
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.643
Subject(s) - metalloproteinase , amyloid precursor protein , protein precursor , alpha secretase , mutant , peptide , biochemistry , p3 peptide , peptide sequence , chemistry , cleavage (geology) , amyloid beta , amyloid precursor protein secretase , protease , wild type , microbiology and biotechnology , biology , enzyme , alzheimer's disease , gene , medicine , paleontology , disease , pathology , fracture (geology)
Background:The amyloid b (Ab) peptide, which is abundantly found in the brains of patients suffering from Alzheimer’s 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 b cleaves APP and liberates soluble N-terminal APP (N-APP) fragments. N-terminal APP fragments of about 11 and 20 kDa were found in human and mouse brain lysates, but not in meprin b-/mouse brain lysates. Methods: Based on a novel proteomics technique termed TAILS (Terminal Amine Isotopic Labeling of Substrates), APP was identified as a substrate for meprin b. Subsequent analysis of APP processing using ELISA, SDS-PAGE, and mass spectrometry revealed cleavage events by meprin b close to the regular BACE1 cleavage site in APP. Results: In this work, we present evidence that meprin b can also process APP in a manner reminiscent of b-secretase. We identified cleavage sites of meprin b in the amyloid b sequence of the wild type and Swedish mutant of APP at positions p1, p2, and p3, thereby generating Ab variants starting at the first, second or third amino acid residue. Importantly, we provide strong evidence that meprin b produces an Ab peptide starting with the glutamate in the third position, indicating that this protease might produce an amino-terminally truncated Ab species. We observed even higher kinetic values for meprin b than BACE1 for both the wild type and the Swedish mutant APP form. This enzymatic activity of meprin b on APP and Ab generation was also observed in the absence of BACE1 and 2, indicating that meprin b acts independently of b-secretase. Conclusions:Our data indicate that meprin b is an enzyme capable of cleaving APP in a b-secretase like manner, probably also at position 674 (Abp3) to expose a glutamate residue, which might be subsequently modified by a glutaminylcyclase to generate pyroglutamate-Ab peptides. Although BACE1 acts as the major b-secretase in vivo generating most of the Ab 1-40/42 peptides, we suggest that meprin b might act as one enzyme responsible for the release of N-terminal truncated Ab species.