PROCESSING OF THE AMYLOID PROTEIN-PRECURSOR TO POTENTIALLY AMYLOIDOGENIC DERIVATIVES

The approximately 120-kilodalton amyloid beta-protein precursor (beta-APP) is processed into a complex set of 8- to 12-kilodalton carboxyl-terminal derivatives that includes potentially amyloidogenic forms with the approximate 4-kilodalton amyloid beta-protein (beta-AP) at or near their amino terminus. In order to determine if these derivatives are processed in a secretory pathway or by the endosomal-lysosomal system, (i) deletion mutants that produce the normal set of carboxyl-terminal derivatives and shortened secreted derivatives were analyzed and (ii) the effect of inhibitors of endosomal-lysosomal processing was examined. In the secretory pathway, cleavage of the beta-APP occurs at a single site within the beta-AP to generate one secreted derivative and one nonamyloidogenic carboxyl-terminal fragment, whereas, in the endosomal-lysosomal system, a complex set of carboxyl-terminal derivatives is produced that includes the potentially amyloidogenic forms.