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ADAM10 is the physiologically relevant, constitutive α‐secretase of the amyloid precursor protein in primary neurons
Author(s) -
Kuhn PeerHendrik,
Wang Huanhuan,
Dislich Bastian,
Colombo Alessio,
Zeitschel Ulrike,
Ellwart Joachim W,
Kremmer Elisabeth,
Roßner Steffen,
Lichtenthaler Stefan F
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.167
Subject(s) - adam10 , proteases , alpha secretase , cleavage (geology) , amyloid precursor protein secretase , amyloid precursor protein , biology , protein precursor , protease , microbiology and biotechnology , biochemistry , metalloproteinase , enzyme , alzheimer's disease , disintegrin , medicine , disease , paleontology , fracture (geology)
The amyloid precursor protein (APP) undergoes constitutive shedding by a protease activity called α‐secretase. This is considered an important mechanism preventing the generation of the Alzheimer's disease amyloid‐β peptide (Aβ). α‐Secretase appears to be a metalloprotease of the ADAM family, but its identity remains to be established. Using a novel α‐secretase‐cleavage site‐specific antibody, we found that RNAi‐mediated knockdown of ADAM10, but surprisingly not of ADAM9 or 17, completely suppressed APP α‐secretase cleavage in different cell lines and in primary murine neurons. Other proteases were not able to compensate for this loss of α‐cleavage. This finding was further confirmed by mass‐spectrometric detection of APP‐cleavage fragments. Surprisingly, in different cell lines, the reduction of α‐secretase cleavage was not paralleled by a corresponding increase in the Aβ‐generating β‐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 γ‐secretase for the cleavage of a C‐terminal APP fragment generated by β‐secretase. We conclude that ADAM10 is the physiologically relevant, constitutive α‐secretase of APP.