%0 Journal Article
%A Kuhn, Peer-Hendrik
%A Wang, Huanhuan
%A Dislich, Bastian
%A Colombo, Alessio
%A Zeitschel, Ulrike
%A Ellwart, Joachim W
%A Kremmer, Elisabeth
%A Rossner, Steffen
%A Lichtenthaler, Stefan
%T ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons.
%J The EMBO journal
%V 29
%N 17
%@ 0261-4189
%C Hoboken, NJ [u.a.]
%I Wiley
%M DZNE-2020-02442
%P 3020-3032
%D 2010
%X The amyloid precursor protein (APP) undergoes constitutive shedding by a protease activity called alpha-secretase. This is considered an important mechanism preventing the generation of the Alzheimer's disease amyloid-beta peptide (Abeta). alpha-Secretase appears to be a metalloprotease of the ADAM family, but its identity remains to be established. Using a novel alpha-secretase-cleavage site-specific antibody, we found that RNAi-mediated knockdown of ADAM10, but surprisingly not of ADAM9 or 17, completely suppressed APP alpha-secretase cleavage in different cell lines and in primary murine neurons. Other proteases were not able to compensate for this loss of alpha-cleavage. This finding was further confirmed by mass-spectrometric detection of APP-cleavage fragments. Surprisingly, in different cell lines, the reduction of alpha-secretase cleavage was not paralleled by a corresponding increase in the Abeta-generating beta-secretase cleavage, revealing that both proteases do not always compete for APP as a substrate. Instead, our data suggest a novel pathway for APP processing, in which ADAM10 can partially compete with gamma-secretase for the cleavage of a C-terminal APP fragment generated by beta-secretase. We conclude that ADAM10 is the physiologically relevant, constitutive alpha-secretase of APP.
%K ADAM Proteins: metabolism
%K ADAM10 Protein
%K Amyloid Precursor Protein Secretases: metabolism
%K Amyloid beta-Protein Precursor: metabolism
%K Animals
%K Cell Line
%K Humans
%K Mass Spectrometry
%K Membrane Proteins: metabolism
%K Mice
%K Neurons: enzymology
%K Neurons: metabolism
%K Amyloid beta-Protein Precursor (NLM Chemicals)
%K Aplp1 protein, mouse (NLM Chemicals)
%K Membrane Proteins (NLM Chemicals)
%K Amyloid Precursor Protein Secretases (NLM Chemicals)
%K ADAM Proteins (NLM Chemicals)
%K ADAM10 Protein (NLM Chemicals)
%K Adam10 protein, mouse (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:20676056
%2 pmc:PMC2944055
%R 10.1038/emboj.2010.167
%U https://pub.dzne.de/record/136120