Regulation of the alternative β-secretase meprin β by ADAM-mediated shedding
Franka Scharfenberg1, Fred Armbrust1, Liana Marengo2
1Unit for Degradomics of the Protease Web, Biochemical Institute, University of Kiel, Kiel, Germany.
Abstract:
Alzheimer's Disease (AD) is the sixth-leading cause of death in industrialized countries. Neurotoxic amyloid-β (Aβ) plaques are one of the pathological hallmarks in AD patient brains. Aβ accumulates in the brain upon sequential, proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretases. However, so far disease-modifying drugs targeting β- and γ-secretase pathways seeking a decrease in the production of toxic Aβ peptides have failed in clinics. It has been demonstrated that the metalloproteinase meprin β acts as an alternative β-secretase, capable of generating truncated Aβ2-x peptides that have been described to be increased in AD patients. This indicates an important β-site cleaving enzyme 1 (BACE-1)-independent contribution of the metalloprotease meprin β within the amyloidogenic pathway and may lead to novel drug targeting avenues. However, meprin β itself is embedded in a complex regulatory network. Remarkably, the anti-amyloidogenic α-secretase a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a direct competitor for APP at the cell surface, but also a sheddase of inactive pro-meprin β. Overall, we highlight the current cellular, molecular and structural understanding of meprin β as alternative β-secretase within the complex protease web, regulating APP processing in health and disease.
Insights
Meprin β, an alternative enzyme, contributes to Alzheimer's disease (AD) pathology by producing amyloid-β (Aβ) peptides independently of BACE-1. Understanding this protease web offers new therapeutic targets for AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is a leading cause of death, characterized by amyloid-β (Aβ) plaques.
- Current treatments targeting amyloid precursor protein (APP) processing by β- and γ-secretases have faced clinical challenges.
- Meprin β, a metalloproteinase, has emerged as a potential alternative β-secretase in AD.
Purpose of the Study:
- To investigate the role of meprin β as an alternative β-secretase in the amyloidogenic pathway.
- To elucidate the regulatory network surrounding meprin β in the context of APP processing.
- To explore novel therapeutic strategies targeting meprin β for Alzheimer's disease.
Main Methods:
- Cellular and molecular biology techniques to study APP processing.
- Biochemical assays to analyze protease activity.
- Structural biology to understand enzyme interactions.
Main Results:
- Meprin β generates truncated Aβ peptides (Aβ2-x) found at elevated levels in AD patients.
- Meprin β functions independently of the primary β-secretase, BACE-1.
- ADAM10, an α-secretase, regulates meprin β activity and competes for APP processing.
Conclusions:
- Meprin β represents a significant BACE-1-independent contributor to the amyloidogenic pathway in AD.
- The complex protease network involving meprin β and ADAM10 offers new avenues for drug development.
- Further research into meprin β's cellular and molecular mechanisms is crucial for advancing AD therapeutics.
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