α-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation

The Swedish mutation within the amyloid precursor protein (APP) causes early-onset Alzheimer's disease due to increased cleavage of APP by BACE1. While beta-secretase shedding of Swedish APP (APPswe) largely results from an activity localized in the late secretory pathway, cleavage of wild-type APP occurs mainly in endocytic compartments. However, we show that liberation of A beta from APPswe is still dependent on functional internalization from the cell surface. Inspite the unchanged overall beta-secretase cleaved soluble APP released from APP(swe) secretion, mutations of the APPswe internalization motif strongly reduced C99 levels and substantially decreased A beta secretion. We point out that alpha-secretase activity-mediated conversion of C99 to C83 is the main cause of this A beta reduction. Furthermore, we demonstrate that alpha-secretase cleavage of C99 even contributes to the reduction of A beta secretion of internalization deficient wild-type APP. Therefore, inhibition of alpha-secretase cleavage increased A beta secretion through diminished conversion of C99 to C83 in APP695, APP695swe or C99 expressing cells.