Journal Article

DZNE-2020-02442

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons.

Kuhn, P.-H. ; Wang, H. ; Dislich, B.DZNE* ; Colombo, A.DZNE* ; Zeitschel, U. ; Ellwart, J. W. ; Kremmer, E. ; Rossner, S. ; Lichtenthaler, S. (Last author)DZNE*

2010
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.1038/emboj.2010.167

Abstract: 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.

Keyword(s): ADAM Proteins: metabolism (MeSH) ; ADAM10 Protein (MeSH) ; Amyloid Precursor Protein Secretases: metabolism (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Animals (MeSH) ; Cell Line (MeSH) ; Humans (MeSH) ; Mass Spectrometry (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Mice (MeSH) ; Neurons: enzymology (MeSH) ; Neurons: metabolism (MeSH) ; Amyloid beta-Protein Precursor ; Aplp1 protein, mouse ; Membrane Proteins ; Amyloid Precursor Protein Secretases ; ADAM Proteins ; ADAM10 Protein ; Adam10 protein, mouse

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Contributing Institute(s):

1. Neuroproteomics (AG Lichtenthaler)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2010

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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