Non-amyloidogenic cleavage of the β-amyloid precursor protein by an integral membrane metalloendopeptidase

Abstract

The β-amyloid precursor protein (β-APP) is a membrane spanning glycoprotein. The small β-protein domain within the precursor is presumed to be the source of amyloid found in plaques characteristic of Alzheimer's disease. The amino terminus of β-APP is released from cells by cleavages that produce both potentially amyloidogenic and nonamyloidogenic fragments of the carboxyl terminus. We developed a cell free system that imposes specificity and co-localization to characterize the proteolytic activity that cleaves the precursor within the β-protein domain. A reporter protein containing the carboxyl-terminal 105 amino acids of β-APP provided a specific substrate for cleavage at Lys16 of the β-protein. The protease inhibitor profile and solubility characteristics of the activity demonstrate the cleavage is produced by an integral membrane metalloendopeptidase.