Journal
EMBO JOURNAL
Volume 29, Issue 17, Pages 3020-3032Publisher
WILEY
DOI: 10.1038/emboj.2010.167
Keywords
ADAM; amyloid precursor protein; neuro-degeneration; proteases; alpha-secretase
Categories
Funding
- Deutsche Forschungsgemeinschaft [SFB596]
- BMBF
- Chinese Scholarship Council
- [RO 2226/10-1]
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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 (Ab). 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 Ab-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. The EMBO Journal (2010) 29, 3020-3032. doi: 10.1038/emboj.2010.167; Published online 30 July 2010
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