Peptides based on the presenilin-APP binding domain inhibit APP processing and Aβ production through interfering with the APP transmembrane domain.
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.
Laboratory for Membrane Trafficking, Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
Cary
C
Esselens
Ragna
R
Sannerud
Rodrigo
R
Gallardo
Veerle
V
Baert
Daniela
D
Kaden
Lutgarde
L
Serneels
Bart
B
De Strooper
Frederic
F
Rousseau
Gerd
G
Multhaup
Joost
J
Schymkowitz
Johannes P M
JP
Langedijk
Wim
W
Annaert
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D053763:Presenilins / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D020349:Surface Plasmon Resonance
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D010455:Peptides; D053763:Presenilins