TY  - JOUR
AU  - Kuhn, Peer-Hendrik
AU  - Wang, Huanhuan
AU  - Dislich, Bastian
AU  - Colombo, Alessio
AU  - Zeitschel, Ulrike
AU  - Ellwart, Joachim W
AU  - Kremmer, Elisabeth
AU  - Rossner, Steffen
AU  - Lichtenthaler, Stefan
TI  - ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons.
JO  - The EMBO journal
VL  - 29
IS  - 17
SN  - 0261-4189
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2020-02442
SP  - 3020-3032
PY  - 2010
AB  - 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.
KW  - ADAM Proteins: metabolism
KW  - ADAM10 Protein
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Animals
KW  - Cell Line
KW  - Humans
KW  - Mass Spectrometry
KW  - Membrane Proteins: metabolism
KW  - Mice
KW  - Neurons: enzymology
KW  - Neurons: metabolism
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Aplp1 protein, mouse (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - ADAM Proteins (NLM Chemicals)
KW  - ADAM10 Protein (NLM Chemicals)
KW  - Adam10 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:20676056
C2  - pmc:PMC2944055
DO  - DOI:10.1038/emboj.2010.167
UR  - https://pub.dzne.de/record/136120
ER  -