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Updated: Mar 25, 2026
Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
Published on: August 28, 2012
Generation of aggregation prone N-terminally truncated amyloid β peptides by meprin β depends on the sequence
Caroline Schönherr1, Jessica Bien1, Simone Isbert1
1Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Duesbergweg 6, 55128, Mainz, Germany.
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.
Insights
Meprin β cleaves amyloid precursor protein (APP), generating N-terminally truncated Aβ2-x variants independently of BACE-1. These variants aggregate more readily and may contribute to Alzheimer's Disease (AD) pathology.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Alzheimer's Disease (AD) involves amyloid precursor protein (APP) processing.
- Meprin β is a metalloprotease with β-secretase-like activity on APP.
- Meprin β predominantly generates N-terminally truncated Aβ2-x variants.
Purpose of the Study:
- Investigate meprin β's role in APP cleavage and Aβ generation.
- Determine if meprin β contributes to AD-relevant peptide formation.
- Analyze the properties of meprin β-generated Aβ variants.
Main Methods:
- Analysis of meprin β knock-out (ko) mice brains.
- Cellular interaction studies of APP and meprin β.
- Assessment of Aβ variant aggregation propensity.
- Studies using Swedish mutant APP (APPswe).
Main Results:
- Increased sAPPα levels observed in meprin β ko mice.
- APP cleavage by meprin β occurs before endocytosis.
- N-terminally truncated Aβ2-40 exhibits higher aggregation than Aβ1-40.
- Meprin β cannot cleave APPswe to generate truncated Aβ.
Conclusions:
- Meprin β is implicated in generating N-terminally truncated Aβ2-x peptides.
- Meprin β functions independently of BACE-1 in APP processing.
- Meprin β-generated Aβ variants may have distinct aggregation properties relevant to AD.
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