AN INCREASED PERCENTAGE OF LONG AMYLOID-BETA PROTEIN SECRETED BY FAMILIAL AMYLOID-BETA PROTEIN-PRECURSOR (BETA-APP(717)) MUTANTS

Normal processing of the amyloid beta protein precursor (beta APP) res ults in secretion of a soluble 4-kilodalton protein essentially identi cal to the amyloid beta protein (A beta) that forms insoluble fibrilla r deposits in Alzheimer's disease. Human neuroblastoma (M17) cells tra nsfected with constructs expressing wild-type beta APP or the beta APP (717) mutants linked to familial Alzheimer's disease were compared by (i) isolation of metabolically labeled 4-kilodalton A beta from condit ioned medium, digestion with cyanogen bromide, and analysis of the car boxyl-terminal peptides released, or (ii) analysis of the A beta in co nditioned medium with sandwich enzyme-linked immunosorbent assays that discriminate Ap(1-40) from the longer AP(1-42). Both methods demonstr ated that the 4-kilodalton Ap released from wild-type beta APP is prim arily but not exclusively AP(1-40). The beta APP(717) mutations, which are located th ree residues carboxyl to A beta(43), consistently caus ed a 1.5- to 1.9-fold increase in the percentage of longer A beta gene rated. Long A beta (for example, A beta(1-42)) forms insoluble amyloid fibrils more rapidly than Ap(1-40). Thus, the beta APP(717) mutants m ay cause Alzheimer's disease because they secrete increased amounts of long A beta, thereby fostering amyloid deposition.