The Metalloprotease Meprin β Is an Alternative β-Secretase of APP
Christoph Becker-Pauly1, Claus U Pietrzik2
1Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel Kiel, Germany.
Abstract:
The membrane bound metalloprotease meprin β is important for collagen fibril assembly in connective tissue formation and for the detachment of the intestinal mucus layer for proper barrier function. Recent proteomic studies revealed dozens of putative new substrates of meprin β, including the amyloid precursor protein (APP). It was shown that APP is cleaved by meprin β in distinct ways, either at the β-secretase site resulting in increased levels of Aβ peptides, or at the N-terminus releasing 11 kDa, and 20 kDa peptide fragments. The latter event was discussed to be rather neuroprotective, whereas the ectodomain shedding of APP by meprin β reminiscent to BACE-1 is in line with the amyloid hypothesis of Alzheimer's disease, promoting neurodegeneration. The N-terminal 11 kDa and 20 kDa peptide fragments represent physiological cleavage products, since they are found in human brains under different diseased or non-diseased states, whereas these fragments are completely missing in brains of meprin β knock-out animals. Meprin β is not only a sheddase of adhesion molecules, such as APP, but was additionally demonstrated to cleave within the prodomain of ADAM10. Activated ADAM10, the α-secretase of APP, is then able to shed meprin β from the cell surface thereby abolishing the β-secretase activity. All together meprin β seems to be a novel player in APP processing events, even influencing other enzymes involved in APP cleavage.
Insights
Meprin β cleaves amyloid precursor protein (APP) in ways that may promote or protect against Alzheimer's disease. This protease also influences other enzymes involved in APP processing, highlighting its complex role.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Meprin β is a metalloprotease involved in tissue formation and barrier function.
- Recent studies identified amyloid precursor protein (APP) as a substrate of meprin β.
- APP processing is central to Alzheimer's disease pathogenesis.
Purpose of the Study:
- To investigate the novel role of meprin β in amyloid precursor protein (APP) processing.
- To elucidate the distinct cleavage patterns of APP by meprin β and their implications.
- To understand how meprin β influences other enzymes involved in APP metabolism.
Main Methods:
- Proteomic analysis to identify meprin β substrates.
- Biochemical assays to characterize APP cleavage by meprin β.
- Analysis of meprin β knock-out animal models.
- Investigation of meprin β interaction with ADAM10.
Main Results:
- Meprin β cleaves APP at the β-secretase site, increasing amyloid-beta (Aβ) peptide levels, potentially promoting neurodegeneration.
- Meprin β also cleaves APP at the N-terminus, releasing neuroprotective fragments.
- These N-terminal fragments are physiological and found in human brains.
- Meprin β cleaves ADAM10, influencing its activity and potentially creating a feedback loop.
- Meprin β modulates APP processing and interacts with key enzymes like BACE-1 and ADAM10.
Conclusions:
- Meprin β is a significant new player in APP processing, with dual roles in Alzheimer's disease pathogenesis.
- Its cleavage of APP can either promote neurodegeneration or yield neuroprotective fragments.
- Meprin β influences the activity of other APP-cleaving enzymes, indicating complex regulatory interactions.
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