α-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation
Article first published online: 5 OCT 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 111, Issue 6, pages 1369–1382, December 2009
How to Cite
Jäger, S., Leuchtenberger, S., Martin, A., Czirr, E., Wesselowski, J., Dieckmann, M., Waldron, E., Korth, C., Koo, E. H., Heneka, M., Weggen, S. and Pietrzik, C. U. (2009), α-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation. Journal of Neurochemistry, 111: 1369–1382. doi: 10.1111/j.1471-4159.2009.06420.x
- Issue published online: 20 NOV 2009
- Article first published online: 5 OCT 2009
- Received June 26, 2009, revised manuscript received September 10, 2009, accepted September 11, 2009.
- Alzheimer’s disease;
- Amyloid precursor protein;
- α-secretase cleavage
The Swedish mutation within the amyloid precursor protein (APP) causes early-onset Alzheimer’s disease due to increased cleavage of APP by BACE1. While β-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 Aβ from APPswe is still dependent on functional internalization from the cell surface. Inspite the unchanged overall β-secretase cleaved soluble APP released from APPswe secretion, mutations of the APPswe internalization motif strongly reduced C99 levels and substantially decreased Aβ secretion. We point out that α-secretase activity-mediated conversion of C99 to C83 is the main cause of this Aβ reduction. Furthermore, we demonstrate that α-secretase cleavage of C99 even contributes to the reduction of Aβ secretion of internalization deficient wild-type APP. Therefore, inhibition of α-secretase cleavage increased Aβ secretion through diminished conversion of C99 to C83 in APP695, APP695swe or C99 expressing cells.