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Regulation of the alternative β-secretase meprin β by ADAM-mediated shedding

  • Franka Scharfenberg
  • Fred Armbrust
  • Liana Marengo
  • Claus PietrzikEmail author
  • Christoph Becker-PaulyEmail author
Review
  • 18 Downloads

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.

Keywords

Meprin β ADAM10 APP β-secretase Alzheimer’s disease 

Abbreviations

AD

Alzheimer’s disease

APP

Amyloid precursor protein

Amyloid-βADAM; a disintegrin and metalloproteinase domain-containing protein

BACE-1

β-Site cleaving enzyme 1

PS1/2

Presenilin 1 and 2

MT-2

Matriptase-2

Notes

Acknowledgements

This work was supported by the Alzheimer Forschung Initiative e.V. (#18007) and the Deutsche Forschungsgemeinschaft (DFG) Project-number 125440785 SFB 877 (Proteolysis as a Regulatory Event in Pathophysiology, Projects A9 and A15) and BE 4086/2-2 (C.B.-P.).

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Unit for Degradomics of the Protease Web, Biochemical InstituteUniversity of KielKielGermany
  2. 2.Institute for PathobiochemistryUniversity Medical Center of the Johannes Gutenberg-University MainzMainzGermany

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