Title: Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation
Authors: Zhou, Lujia
Brouwers, Nathalie
Benilova, Iryna
Vandersteen, Annelies
Mercken, Marc
Van Laere, Koen
Philip Van Damme, Philip
Demedts, David
Van Leuven, Fred
Sleegers, Kristel
Broersen, Kerensa
Van Broeckhoven, Christine
Vandenberghe, Rik
De Strooper, Bart # ×
Issue Date: Mar-2011
Publisher: Wiley-Blackwell Publishing Ltd.
Series Title: EMBO Molecular Medicine vol:3 issue:5 pages:291-302
Article number: 10.1002/emmm.201100138
Abstract: BACE1 cleaves the amyloid precursor protein (APP) at the β-cleavage site (Met(671) -Asp(672) ) to initiate the generation of amyloid peptide Aβ. BACE1 is also known to cleave APP at a much less well-characterized β'-cleavage site (Tyr(681) -Glu(682) ). We describe here the identification of a novel APP mutation E682K located at this β'-site in an early onset Alzheimer's disease (AD) case. Functional analysis revealed that this E682K mutation blocked the β'-site and shifted cleavage of APP to the β-site, causing increased Aβ production. This work demonstrates the functional importance of APP processing at the β'-site and shows how disruption of the balance between β- and β'-site cleavage may enhance the amyloidogenic processing and consequentially risk for AD. Increasing exon- and exome-based sequencing efforts will identify many more putative pathogenic mutations without conclusive segregation-based evidence in a single family. Our study shows how functional analysis of such mutations allows to determine the potential pathogenic nature of these mutations. We propose to classify the E682K mutation as probable pathogenic awaiting further independent confirmation of its association with AD in other patients. →See accompanying Closeup by Rita Guerreiro and John Hardy DOI 10.1002/emmm201100139.
ISSN: 1757-4676
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for the Research of Neurodegenerative Diseases
Nuclear Medicine & Molecular Imaging
Research Group Experimental Neurology
Laboratory for Cognitive Neurology
Laboratory for Neurobiology
× corresponding author
# (joint) last author

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