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Title: Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability
Authors: De Jonghe, Chantal
Esselens, Carl
Kumar-Singh, S
Craessaerts, Kathleen
Serneels, Lutgarde
Checler, F
Annaert, Wim
Van Broeckhoven, C
De Strooper, Bart # ×
Issue Date: Aug-2001
Series Title: Human Molecular Genetics vol:10 issue:16 pages:1665-71
Abstract: Release of amyloid beta (Abeta) from the amyloid precursor protein (APP) requires cleavages by beta- and gamma-secretases and plays a crucial role in Alzheimer's disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the beta-, alpha- and particular gamma-secretase cleavage sites. We systematically compare in primary neurons the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the gamma-secretase cleavage site. We confirm and extend previous observations showing that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) affect gamma-secretase cleavage causing an increased relative ratio of Abeta42 to Abeta40. Taking advantage of these extended series of APP mutations we were able to demonstrate an inverse correlation between these ratios and the age at onset of the disease in the different families. In addition, a subset of mutations caused the accumulation of APP C-terminal fragments indicating that these mutations also influence the stability of APP C-terminal fragments. However, it is unlikely that these fragments contribute significantly to the disease process.
ISSN: 0964-6906
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Laboratory of Membrane Trafficking
Laboratory for the Research of Neurodegenerative Diseases
Department of Human Genetics - miscellaneous
Materials Technology TC, Campus Group T Leuven
Technologiecluster Materialentechnologie
× corresponding author
# (joint) last author

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