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Title: Peptides based on the presenilin-APP binding domain inhibit APP processing and Aβ production through interfering with the APP transmembrane domain
Authors: Esselens, Carl
Sannerud, Ragna
Gallardo, Rodrigo
Baert, Veerle
Kaden, Daniela
Serneels, Lutgarde
De Strooper, Bart
Rousseau, Frederic
Multhaup, Gerd
Schymkowitz, Joost
Langedijk, Johannes P M
Annaert, Wim # ×
Issue Date: Sep-2012
Publisher: The Federation of American Societies for Experimental Biology
Series Title: FASEB Journal vol:26 issue:9 pages:3765-3778
Abstract: Presenilins (PSENs) form the catalytic component of the γ-secretase complex, responsible for intramembrane proteolysis of amyloid precursor protein (APP) and Notch, among many other membrane proteins. Previously, we identified a PSEN1-binding domain in APP, encompassing half of the transmembrane domain following the amyloid β (Aβ) sequence. Based on this, we designed peptides mimicking this interaction domain with the aim to selectively block APP processing and Aβ generation through interfering with enzyme-substrate binding. We identified a peptide sequence that, when fused to a virally derived translocation peptide, significantly lowered Aβ production (IC(50): 317 nM) in cell-free and cell-based assays using APP-carboxy terminal fragment as a direct γ-secretase substrate. Being derived from the APP sequence, this inhibitory peptide did not affect NotchΔE γ-cleavage, illustrating specificity and potential therapeutic value. In cell-based assays, the peptide strongly suppressed APP shedding, demonstrating that it exerts the inhibitory effect already upstream of γ-secretase, most likely through steric hindrance.-Esselens, C., Sannerud, R., Gallardo, R., Baert, V., Kaden, D., Serneels, L., De Strooper, B., Rousseau, F., Multhaup, G., Schymkowitz, J., Langedijk, J. P. M., Annaert, W. Peptides based on the presenilin-APP binding domain inhibit APP processing and Aβ production through interfering with the APP transmembrane domain.
URI: 
ISSN: 0892-6638
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for the Research of Neurodegenerative Diseases
Switch Laboratory
Laboratory of Membrane Trafficking
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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