ALTERED CLEAVAGE AND SECRETION OF A RECOMBINANT BETA-APP BEARING THE SWEDISH FAMILIAL ALZHEIMERS-DISEASE MUTATION

Mutations within the beta-amyloid precursor protein gene cosegregate w ith the early-onset form of familial Alzheimer's Disease (FAD). It is not known how these mutations result in disease; however, one early-on set AD mutation in a Swedish kindred increases potentially amyloidogen ic fragments and beta-protein production in cells expressing the mutan t beta-APP. Using a novel recombinant reporter system we found a quali tative change in the secreted product, from cleavage within the beta-p rotein sequence to cleavage near the N-terminal region of the beta-pro tein, even though the total amount of secreted mutant product is simil ar to wild-type. The results suggest that the increased formation of p otentially amyloidogenic fragments in cells expressing the Swedish FAD occurs by enzymatic cleavage in the secretory pathway. Alterations in the secretory process may predispose an individual to AD.