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Title: Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
Authors: De Strooper, Bart ×
Saftig, P
Craessaerts, Kathleen
Vanderstichele, H
Guhde, G
Annaert, Wim
Von Figura, K
Van Leuven, Freddy #
Issue Date: Feb-1998
Series Title: Nature vol:391 issue:6665 pages:387-90
Abstract: Point mutations in the presenilin-1 gene (PS1) are a major cause of familial Alzheimer's disease. They result in a selective increase in the production of the amyloidogenic peptide amyloid-beta(1-42) by proteolytic processing of the amyloid precursor protein (APP). Here we investigate whether PS1 is also involved in normal APP processing in neuronal cultures derived from PS1-deficient mouse embryos. Cleavage by alpha- and beta-secretase of the extracellular domain of APP was not affected by the absence of PS1, whereas cleavage by gamma-secretase of the transmembrane domain of APP was prevented, causing carboxyl-terminal fragments of APP to accumulate and a fivefold drop in the production of amyloid peptide. Pulse-chase experiments indicated that PS1 deficiency specifically decreased the turnover of the membrane-associated fragments of APP. As in the regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor, PS1 appears to facilitate a proteolytic activity that cleaves the integral membrane domain of APP. Our results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.
ISSN: 0028-0836
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Associated Laboratories - miscellaneous (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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