CLEAVAGE AT THE N-TERMINAL SITE OF ALZHEIMER AMYLOID BETA/A4 PROTEIN IS ESSENTIAL FOR ITS SECRETION

To characterize the secretory pathway of Alzheimer amyloid beta/A4 protein (beta/A4), mutated cDNAs of amyloid precursor protein (APP) were expressed transiently in COS cells. Although the expression of C100 (Met(671)-Asn(770)) resulted in the secretion of beta/A4-like peptide, the cells expressing the mutated APPs with the longer N-terminal domain beyond beta/A4 sequence secreted little beta/A4-like peptide. The C-terminal domain truncated APPs, with a stop codon at the end of beta/A4 sequence or the predicted membrane spanning domain produced little beta/A4-like peptide. When beta/A4 was expressed with direct addition of the signal sequence, beta/A4-like peptide was found in the cell lysate but little of it was secreted. Hence, the secretion of beta/A4 was started initially by cleavage at the N-terminal site of beta/A4, although cleavage at its C-terminal site was also necessary for its secretion. (C) 1994 Academic Press, Inc.