title: Generation of aggregation prone N-terminally truncated amyloid β peptides by meprin β depends on the sequence specificity at the cleavage site.
abstract: BACKGROUND
  The metalloprotease meprin β cleaves the Alzheimer's Disease (AD) relevant amyloid precursor protein (APP) as a β-secretase reminiscent of BACE-1, however, predominantly generating N-terminally truncated Aβ2-x variants.
  
  
  RESULTS
  Herein, we observed increased endogenous sAPPα levels in the brains of meprin β knock-out (ko) mice compared to wild-type controls. We further analyzed the cellular interaction of APP and meprin β and found that cleavage of APP by meprin β occurs prior to endocytosis. The N-terminally truncated Aβ2-40 variant shows increased aggregation propensity compared to Aβ1-40 and acts even as a seed for Aβ1-40 aggregation. Additionally, we observed that different APP mutants affect the catalytic properties of meprin β and that, interestingly, meprin β is unable to generate N-terminally truncated Aβ peptides from Swedish mutant APP (APPswe).
  
  
  CONCLUSIONS
  Concluding, we propose that meprin β may be involved in the generation of N-terminally truncated Aβ2-x peptides of APP, but acts independently from BACE-1.
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Duesbergweg 6, 55128, Mainz, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schönherr
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Duesbergweg 6, 55128, Mainz, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bien
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Duesbergweg 6, 55128, Mainz, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Isbert
authors.affiliation: Institute of Biochemistry, Unit for Degradomics of the Protease Web, Christian-Albrechts-University, Otto-Hahn-Platz 9, 24118, Kiel, Germany.
authors.forename: Rielana
authors.initials: R
authors.lastname: Wichert
authors.affiliation: Institute of Biochemistry, Unit for Degradomics of the Protease Web, Christian-Albrechts-University, Otto-Hahn-Platz 9, 24118, Kiel, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Prox
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Altmeppen
authors.affiliation: Department of Neurology, Molecular Cell Biology, University of Bonn, 53127, Bonn, Germany.
authors.forename: Sathish
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Neurology, Molecular Cell Biology, University of Bonn, 53127, Bonn, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) and Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, 81675, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.affiliation: Department of Neuropathology, Heinrich Heine University, 40225, Duesseldorf, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.affiliation: Institute of Biochemistry, Unit for Degradomics of the Protease Web, Christian-Albrechts-University, Otto-Hahn-Platz 9, 24118, Kiel, Germany. cbeckerpauly@biochem.uni-kiel.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Duesbergweg 6, 55128, Mainz, Germany. pietrzik@uni-mainz.de.
authors.forename: Claus U
authors.initials: CU
authors.lastname: Pietrzik
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D008666:Metalloendopeptidases; C095663:meprin B