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

Background: The metalloprotease meprin beta cleaves the Alzheimer's Disease (AD) relevant amyloid precursor protein (APP) as a beta-secretase reminiscent of BACE-1, however, predominantly generating N-terminally truncated A beta 2-x variants. Results: Herein, we observed increased endogenous sAPPa levels in the brains of meprin beta knock-out (ko) mice compared to wild-type controls. We further analyzed the cellular interaction of APP and meprin beta and found that cleavage of APP by meprin beta occurs prior to endocytosis. The N-terminally truncated A beta 2-40 variant shows increased aggregation propensity compared to A beta 1-40 and acts even as a seed for A beta 1-40 aggregation. Additionally, we observed that different APP mutants affect the catalytic properties of meprin beta and that, interestingly, meprin beta is unable to generate N-terminally truncated A beta peptides from Swedish mutant APP (APPswe). Conclusion: Concluding, we propose that meprin beta may be involved in the generation of N-terminally truncated A beta 2-x peptides of APP, but acts independently from BACE-1.