Metalloprotease meprin beta generates nontoxic N-terminal amyloid precursor protein fragments in vivo.

ABSTRACT: Identification of physiologically relevant substrates is still the most challenging part in protease research for understanding the biological activity of these enzymes. The zinc-dependent metalloprotease meprin ? is known to be expressed in many tissues with functions in health and disease. Here, we demonstrate unique interactions between meprin ? and the amyloid precursor protein (APP). Although APP is intensively studied as a ubiquitously expressed cell surface protein, which is involved in Alzheimer disease, its precise physiological role and relevance remain elusive. Based on a novel proteomics technique termed terminal amine isotopic labeling of substrates (TAILS), APP was identified as a substrate for meprin ?. Processing of APP by meprin ? was subsequently validated using in vitro and in vivo approaches. N-terminal APP fragments of about 11 and 20 kDa were found in human and mouse brain lysates but not in meprin ?(-/-) mouse brain lysates. Although these APP fragments were in the range of those responsible for caspase-induced neurodegeneration, we did not detect cytotoxicity to primary neurons treated by these fragments. Our data demonstrate that meprin ? is a physiologically relevant enzyme in APP processing.

SUBMITTER: Jefferson T 

PROVIDER: S-EPMC3149364 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature