alpha-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Abeta 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 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.
Molecular Neurodegeneration Group, Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg-University Mainz, Mainz, Germany.
Sebastian
S
Jäger
Stefanie
S
Leuchtenberger
Anne
A
Martin
Eva
E
Czirr
Johanna
J
Wesselowski
Marco
M
Dieckmann
Elaine
E
Waldron
Carsten
C
Korth
Edward H
EH
Koo
Michael
M
Heneka
Sascha
S
Weggen
Claus U
CU
Pietrzik
D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019921:Biotinylation / Q000379:methods; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases