Aβ42-oligomer Interacting Peptide (AIP) neutralizes toxic amyloid-β42 species and protects synaptic structure and function.
The amyloid-β42 (Aβ42) peptide is believed to be the main culprit in the pathogenesis of Alzheimer disease (AD), impairing synaptic function and initiating neuronal degeneration. Soluble Aβ42 oligomers are highly toxic and contribute to progressive neuronal dysfunction, loss of synaptic spine density, and affect long-term potentiation (LTP). We have characterized a short, L-amino acid Aβ-oligomer Interacting Peptide (AIP) that targets a relatively well-defined population of low-n Aβ42 oligomers, rather than simply inhibiting the aggregation of Aβ monomers into oligomers. Our data show that AIP diminishes the loss of Aβ42-induced synaptic spine density and rescues LTP in organotypic hippocampal slice cultures. Notably, the AIP enantiomer (comprised of D-amino acids) attenuated the rough-eye phenotype in a transgenic Aβ42 fly model and significantly improved the function of photoreceptors of these flies in electroretinography tests. Overall, our results indicate that specifically "trapping" low-n oligomers provides a novel strategy for toxic Aβ42-oligomer recognition and removal.
Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada.
Christian
C
Barucker
Institute of Medical Physics and Biophysics, Charite-Universitätsmedizin, Germany.
Heiko J
HJ
Bittner
Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada.
Philip K-Y
PK
Chang
Department of Neurology and Neurosurgery, Montreal, McGill Centre for Research in Neuroscience, Canada.
Scott
S
Cameron
Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada.
Mark A
MA
Hancock
Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada.
Filip
F
Liebsch
Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada.
Shireen
S
Hossain
Institut für Chemie und Biochemie, Freie Universität Berlin, Germany.
Anja
A
Harmeier
Department of Neurology and Neurosurgery, Montreal, McGill Centre for Research in Neuroscience, Canada.
Hunter
H
Shaw
Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada.
François M
FM
Charron
Department of Physics &IRIS Adlershof, Humboldt-Universität zu Berlin, Germany.
Manuel
M
Gensler
Institut für Chemie und Biochemie, Freie Universität Berlin, Germany.
Paul
P
Dembny
Department of Physics &IRIS Adlershof, Humboldt-Universität zu Berlin, Germany.
Wei
W
Zhuang
Neurowissenschaftliches Forschungszentrum, Charite-Universitätsmedizin, German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
Dietmar
D
Schmitz
Department of Physics &IRIS Adlershof, Humboldt-Universität zu Berlin, Germany.
Jürgen P
JP
Rabe
Department of Neurology and Neurosurgery, Montreal, McGill Centre for Research in Neuroscience, Canada.
Yong
Y
Rao
Max-Planck-Institute for Molecular Genetics, Berlin, Germany.
Rudi
R
Lurz
Institute of Medical Physics and Biophysics, Charite-Universitätsmedizin, Germany.
Peter W
PW
Hildebrand
Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada.
R Anne
RA
McKinney
Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada.|Institut für Chemie und Biochemie, Freie Universität Berlin, Germany.
Gerhard
G
Multhaup
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)