Characterization of the ectodomain shedding of the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1)

Abstract

Generation of the amyloid peptide through proteolytic processing of the amyloid precursor protein by β- and γ-secretases is central to the etiology of Alzheimer's disease. β-secretase, known more widely as the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), has been identified as a transmembrane aspartic proteinase, and its ectodomain has been reported to be cleaved and secreted from cells in a soluble form. The extracellular domains of many diverse proteins are known to be cleaved and secreted from cells by a process known as ectodomain shedding. Here we confirm that the ectodomain of BACE1 is secreted from cells and that this processing is up-regulated by agents that activate protein kinase C. A metalloproteinase is involved in the cleavage of BACE1 as hydroxamic acid-based metalloproteinase inhibitors abolish the release of shed BACE1. Using potent and selective inhibitors, we demonstrate that ADAM10 is a strong candidate for the BACE1 sheddase. In addition, we show that the BACE1 sheddase is distinct from α-secretase and, importantly, that inhibition of BACE1 shedding does not influence amyloid precursor protein processing at the β-site.