[en] 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 Abeta 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 Abeta secretion. We point out that alpha-secretase activity-mediated conversion of C99 to C83 is the main cause of this Abeta reduction. Furthermore, we demonstrate that alpha-secretase cleavage of C99 even contributes to the reduction of Abeta secretion of internalization deficient wild-type APP. Therefore, inhibition of alpha-secretase cleavage increased Abeta secretion through diminished conversion of C99 to C83 in APP695, APP695swe or C99 expressing cells.
Disciplines :
Neurologie
Auteur, co-auteur :
Jäger, Sebastian; Molecular Neurodegeneration Group, Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg-University Mainz, Mainz, Germany
Leuchtenberger, Stefanie; Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
Martin, Anne; Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes-Gutenberg-University Mainz, D-55099 Mainz, Germany
Czirr, Eva; Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
Wesselowski, Johanna; Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes-Gutenberg-University Mainz, D-55099 Mainz, Germany
Dieckmann, Marco; Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
Waldron, Elaine; Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes-Gutenberg-University Mainz, D-55099 Mainz, Germany
Korth, Carsten; Institute of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
Koo, Edward H; Department of Neurosciences, University of California, United States
HENEKA, Michael ; Department of Neurology, Clinical Neuroscience, University of Bonn, Bonn, Germany
Weggen, Sascha; Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
Pietrzik, Claus U; Institute of Physiological Chemistry and Pathobiochemistry, Molecular Neurodegeneration, Johannes-Gutenberg-University Mainz, D-55099 Mainz, Germany
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
alpha-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Abeta generation.
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