Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons

EMBO J. 2010 Sep 1;29(17):3020-32. Epub 2010 Jul 30.

Authors/Editors: Kuhn PH
Wang H
Dislich B
Colombo A
Zeitschel U
Ellwart JW
Kremmer E
Rossner S
Publication Date: 2010
Type of Publication: Journal Article
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.


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