Journal Article

Generation of aggregation prone N-terminally truncated amyloid β peptides by meprin β depends on the sequence specificity at the cleavage site

Altmeppen, Hermann, Pietrzik, Claus U., Wichert, Rielana, Becker-Pauly, Christoph, Bien, Jessica, Walter, Jochen, Isbert, Simone, Prox, Johannes, Kumar, Sathish, Lichtenthaler, Stefan F., Glatzel, Markus, Schönherr, Caroline, Weggen, Sascha

2016

Overview

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). Conclusion 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.

• Publisher: BioMed Central,Springer Nature B.V
• Subject: Alzheimer Disease - metabolism / Amyloid beta-Peptides - metabolism / Amyloid beta-Protein Precursor - metabolism / Amyloid Precursor Protein Secretases - metabolism / Animals / Aspartic Acid Endopeptidases - metabolism / Biomedical and Life Sciences / Biomedicine / Brain - metabolism / Metalloendopeptidases - metabolism / Mice, Knockout / Molecular Medicine / Neurology / Neurons - metabolism / Neurosciences / Research Article