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Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation.
EMBO Mol Med. 2011 May; 3(5):291-302.EM

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.

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Authors+Show Affiliations

Zhou L
Department for Developmental and Molecular Genetics, VIB, Leuven, Belgium.
Brouwers N
No affiliation info available
Benilova I
No affiliation info available
Vandersteen A
No affiliation info available
Mercken M
No affiliation info available
Van Laere K
No affiliation info available
Van Damme P
No affiliation info available
Demedts D
No affiliation info available
Van Leuven F
No affiliation info available
Sleegers K
No affiliation info available
Broersen K
No affiliation info available
Van Broeckhoven C
No affiliation info available
Vandenberghe R
No affiliation info available
De Strooper B
No affiliation info available

MeSH

Amino Acid SubstitutionAmyloid Precursor Protein SecretasesAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAspartic Acid EndopeptidasesHumansMutant ProteinsMutation, Missense

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21500352

Citation

Zhou, Lujia, et al. "Amyloid Precursor Protein Mutation E682K at the Alternative Β-secretase Cleavage Β'-site Increases Aβ Generation." EMBO Molecular Medicine, vol. 3, no. 5, 2011, pp. 291-302.
Zhou L, Brouwers N, Benilova I, et al. Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation. EMBO Mol Med. 2011;3(5):291-302.
Zhou, L., Brouwers, N., Benilova, I., Vandersteen, A., Mercken, M., Van Laere, K., Van Damme, P., Demedts, D., Van Leuven, F., Sleegers, K., Broersen, K., Van Broeckhoven, C., Vandenberghe, R., & De Strooper, B. (2011). Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation. EMBO Molecular Medicine, 3(5), 291-302. https://doi.org/10.1002/emmm.201100138
Zhou L, et al. Amyloid Precursor Protein Mutation E682K at the Alternative Β-secretase Cleavage Β'-site Increases Aβ Generation. EMBO Mol Med. 2011;3(5):291-302. PubMed PMID: 21500352.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation. AU - Zhou,Lujia, AU - Brouwers,Nathalie, AU - Benilova,Iryna, AU - Vandersteen,Annelies, AU - Mercken,Marc, AU - Van Laere,Koen, AU - Van Damme,Philip, AU - Demedts,David, AU - Van Leuven,Fred, AU - Sleegers,Kristel, AU - Broersen,Kerensa, AU - Van Broeckhoven,Christine, AU - Vandenberghe,Rik, AU - De Strooper,Bart, Y1 - 2011/04/15/ PY - 2010/12/20/received PY - 2011/02/04/revised PY - 2011/03/06/accepted PY - 2011/4/19/entrez PY - 2011/4/19/pubmed PY - 2011/8/10/medline SP - 291 EP - 302 JF - EMBO molecular medicine JO - EMBO Mol Med VL - 3 IS - 5 N2 - 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. SN - 1757-4684 UR - https://www.unboundmedicine.com/medline/citation/21500352/Amyloid_precursor_protein_mutation_E682K_at_the_alternative_β_secretase_cleavage_β'_site_increases_Aβ_generation_ L2 - https://doi.org/10.1002/emmm.201100138 DB - PRIME DP - Unbound Medicine ER -