Journal Article

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

Pietrzik, Claus, Marengo, Liana, Scharfenberg, Franka, Armbrust, Fred, Becker-Pauly, Christoph

2019

Overview

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.

• Publisher: Springer Nature B.V
• Subject: Alzheimer's disease / Amyloid precursor protein / Amyloidogenesis / Brain / Cell surface / Cellular structure / Drug delivery / Neurodegenerative diseases / Neurotoxicity / Peptides / Proteins / Proteolysis / Secretase / Senile plaques / β-Amyloid / β-Site APP-cleaving enzyme 1 / β-Site APP-cleaving enzymes