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Peptides based on the presenilin‐APP binding domain inhibit APP processing and Aβ production through interfering with the APP transmembrane domain
Author(s) -
Esselens Cary,
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
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-201368
Subject(s) - presenilin , domain (mathematical analysis) , transmembrane domain , transmembrane protein , chemistry , microbiology and biotechnology , biology , biochemistry , membrane , medicine , alzheimer's disease , receptor , disease , mathematical analysis , mathematics
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. FASEB J. 26, 3765–3778 (2012). www.fasebj.org