The mutation in amyloid precursor protein inhibits both alpha- and beta-secretion

beta-amyloid protein (A beta) is produced from amyloid precursor protein (APP) is mainly secreted after cleavage within the beta-amyloid protein (A beta) sequence precluding A beta production. Stimulation of APP secretion inhibits A beta production in some cultured cells, which suggests that the relationship between these two processes is alternate. In this study, we investigated the effect of the inhibition of APP secretion on A beta production using stable transformants of glioma U251 which express the mutant APP695 with a lysine-to-valine substitution at residue 612. Immunoprecipitation analysis showed that the mutant APP695 was secreted much less compared to the wild protein. The respective ratios of the amount of secreted APP to that of cellular APP for the mutant and wild forms were 0.11 and 1.01. A beta production by the mutant APP also was suppressed. The respective ratios of the amount of secreted A beta to that of cellular APP for the mutant and wild forms were 0.022 and 0.13. Both processes of APP secretion and A beta production could be inhibited simultaneously by the mutation, which suggests that they are not always alternate. Immunocytochemistry showed that the mutant APP was not transported to the cell membrane. Both APP secretory processes may require the transportation of APP to the cell membrane.