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α‐secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation
Author(s) -
Jäger Sebastian,
Leuchtenberger Stefanie,
Martin Anne,
Czirr Eva,
Wesselowski Johanna,
Dieckmann Marco,
Waldron Elaine,
Korth Carsten,
Koo Edward H.,
Heneka Michael,
Weggen Sascha,
Pietrzik Claus U.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06420.x
Subject(s) - internalization , secretion , amyloid precursor protein , microbiology and biotechnology , chemistry , endocytic cycle , amyloid precursor protein secretase , p3 peptide , alpha secretase , cleavage (geology) , medicine , alzheimer's disease , cell , biology , endocytosis , biochemistry , disease , paleontology , fracture (geology)
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 APP swe 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.