NON-AMYLOIDOGENIC CLEAVAGE OF THE BETA-AMYLOID PRECURSOR PROTEIN BY AN INTEGRAL MEMBRANE METALLOENDOPEPTIDASE

The beta-amyloid precursor protein (beta-APP) is a membrane spanning g lycoprotein. The small beta-protein domain within the precursor is pre sumed to be the source of amyloid found in plaques characteristic of A lzheimer's disease. The amino terminus of beta-APP is released from ce lls by cleavages that produce both potentially amyloidogenic and nonam yloidogenic fragments of the carboxyl terminus. We developed a cell fr ee system that imposes specificity and co-localization to characterize the proteolytic activity that cleaves the precursor within the beta-p rotein domain. A reporter protein containing the carboxyl-terminal 105 amino acids of beta-APP provided a specific substrate for cleavage at Lys16 of the beta-protein. The protease inhibitor profile and solubil ity characteristics of the activity demonstrate the cleavage is produc ed by an integral membrane metalloendopeptidase.