Alpha-secretase mediated conversion of the amyloid precursor protein derived membrane stub c99 to c83 limits a beta generation
Journal of neurochemistry. Bd. 111. H. 6. Oxford: Wiley-Blackwell 2009 S. 1369 - 1382
Erscheinungsjahr: 2009
ISBN/ISSN: 0022-3042
Publikationstyp: Zeitschriftenaufsatz
Sprache: Englisch
Doi/URN: 10.1111/j.1471-4159.2009.06420.x
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Inhaltszusammenfassung
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...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.» weiterlesen» einklappen
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Medizin
