Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursor

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the extracellular deposition of amyloid beta-protein (A beta), a molecule produced by post-translational processing of the beta-amyloid precursor protein (beta APP). Mutations within the gene encoding beta APP have been linked to early onset forms of AD, but the pathogenetic mechanism(s) producing the phenotype are unknown. We analyzed the effects on beta APP processing in vitro of a naturally occurring Ala-->Gly mutation at position 692 of beta APP770 (A692G) (Hendriks, L., Duijin, C., Cras, P., Cruts, M., van Hul, W., van Harskamp, F., Warren, A., McInnis, M., Antonarakis, S., Martin, J.-J., Hofman, A., and van Broeckhoven, C. (1992) Nature Genet. 1, 218-221), as well as the effects of five genetically engineered mutations at or near this site. Substitution of glycine or proline for Ala692, or for Phe690, produced relative increases in secretion of A beta and relative decreases in secretion of the p3 peptide(s) arising after alpha-secretase generation of soluble APP (APPs). The Phe690-->Pro substitution also resulted in the synthesis of truncated APPs molecules. The structurally conservative substitutions Ala692-->Val and Phe690-->Tyr did not exhibit these effects. Certain of the substitutions also resulted in the production of a minor peptides, previously undescribed in vitro, beginning at Ala2, Lys16, and Phe19 of A beta. These data show that beta APP mutations carboxyl-terminal to alpha-secretase and beta-secretase cleavage sites can exert strong control over beta APP processing. Increased secretion of A beta may accelerate amyloidogenesis by providing more precursors for aggregation. It is also possible that truncated A beta peptides resulting from several of these mutations may accelerate amyloidogenesis through self-aggregation and/or seeding the fibrillogenesis of longer, more abundant A beta species.