Amyloid precursor protein mutation E682K at the alternative beta-secretase cleavage beta '-site increases A beta generation

作者：Zhou Lujia; Brouwers Nathalie; Benilova Iryna; Vandersteen Annelies; Mercken Marc; Van Laere Koen; Van Damme Philip; Demedts David; Van Leuven Fred; Sleegers Kristel; Broersen Kerensa; Van Broeckhoven Christine; Vandenberghe Rik; De Strooper Bart^*

来源：EMBO Molecular Medicine, 2011, 3(5): 291-302.

DOI：10.1002/emmm.201100138

• Alzheimer's disease
• APP
• A beta
• BACE1
• beta '-site cleavage
• E682K

BACE1 cleaves the amyloid precursor protein (APP) at the beta-cleavage site (Met(671)-Asp(672)) to initiate the generation of amyloid peptide A beta. BACE1 is also known to cleave APP at a much less well-characterized IT-cleavage site (Tyr(681)-Glu(682)). We describe here the identification of a novel APP mutation E682K located at this beta'-site in an early onset Alzheimer's disease (AD) case. Functional analysis revealed that this E682K mutation blocked the beta'-site and shifted cleavage of APP to the beta-site, causing increased A beta production. This work demonstrates the functional importance of APP processing at the beta'-site and shows how disruption of the balance between beta- and beta'-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.

• 出版日期2011-5
• 单位KU Leuven