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Kuhn, P.H.* ; Wang, H.* ; Dislich, B.* ; Colombo, A.* ; Zeitschel, U.* ; Ellwart, J.W. ; Kremmer, E. ; Rossner, S.* ; Lichtenthaler, S.F.*

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

EMBO J. 29, 3020-3032 (2010)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords ADAM; amyloid precursor protein; neuro-degeneration; proteases; alpha-secretase; NECROSIS-FACTOR-ALPHA; METALLOPROTEASE-DISINTEGRIN MDC9; ONSET ALZHEIMERS-DISEASE; BETA-SECRETASE; CONVERTING-ENZYME; HIPPOCAMPAL-NEURONS; CLEAVAGE; APP; ECTODOMAIN; PATHWAY
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Journal EMBO Journal, The
Quellenangaben Volume: 29, Issue: 17, Pages: 3020-3032 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Heidelberg, Germany
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)