Generation of aggregation prone N-terminally truncated amyloid β peptides by meprin β depends on the sequence specificity at the cleavage site. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Schönherr, Caroline; Bien, Jessica; Isbert, Simone; Wichert, Rielana; Prox, Johannes; Altmeppen, Hermann; Kumar, Sathish; Walter, Jochen; Lichtenthaler, Stefan; Weggen, Sascha; Glatzel, Markus; Becker-Pauly, Christoph; Pietrzik, Claus
• Is Part Of: Molecular neurodegeneration. Volume 11:Issue 1(2016)
• Page Start: 1
• Page End: 16
• Publication Date: 2016-12
• Subjects: Alzheimer's Disease -- Meprin β -- Metalloprotease -- Amyloid precursor protein -- Amyloid β -- N-terminal truncation -- APP mutations -- Protein-protein interaction -- Cell surface protein; Neurobiology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1186/s13024-016-0084-5
• Languages: English
• ISSNs: 1750-1326

Abstract

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). 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.