Peptide Blockers of the Inhibition of Neuronal Nicotinic Acetylcholine Receptors by Amyloid β

Alzheimer disease (AD) is characterized by accumulation of the neurotoxic amyloid β peptide (Aβ) and by the loss of cholinergic neurons and nicotinic acetylcholine receptors (nAChRs) throughout the brain. Direct inhibition of nAChRs by Aβ has also been suggested to contribute to cholinergic dysfunct...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-09, Vol.280 (35), p.31085-31090
Main Authors: Magdesian, Margaret H., Nery, Arthur A., Martins, A. Henrique B., Juliano, Maria Aparecida, Juliano, Luiz, Ulrich, Henning, Ferreira, Sérgio T.
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Amino Acid Sequence
Amyloid beta-Peptides - metabolism
Animals
Carbachol - metabolism
Cholinergic Agonists - metabolism
Electrophysiology
Humans
Models, Molecular
Neurons - metabolism
PC12 Cells
Peptide Library
Peptides - metabolism
Protein Structure, Tertiary
Rats
Receptors, Nicotinic - metabolism
Sequence Alignment
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Summary:Alzheimer disease (AD) is characterized by accumulation of the neurotoxic amyloid β peptide (Aβ) and by the loss of cholinergic neurons and nicotinic acetylcholine receptors (nAChRs) throughout the brain. Direct inhibition of nAChRs by Aβ has also been suggested to contribute to cholinergic dysfunction in AD. In an effort to find ligands capable of blocking Aβ-induced inhibition of nAChRs, we have screened a phage display library to identify peptides that bind to Aβ. Using this approach, we identified a heptapeptide denoted IQ, which binds with nanomolar affinity to Aβ and is homologous to the acetylcholine-binding protein and to most subtypes of nAChRs. Rapid kinetic whole-cell current-recording measurements showed that Aβ inhibits nAChR function in a dose-dependent manner in neuronal differentiated PC12 cells and that nanomolar concentrations of IQ completely block the inhibition by Aβ. These results indicate that the Aβ binding site in nAChRs is homologous to the IQ peptide and that this is a relevant target for Aβ neurotoxicity in AD and, more generally, for the regulation of nAChR function by soluble Aβ in a physiological context. Furthermore, the results suggest that the IQ peptide may be a lead for the development of novel drugs to block the inhibition of nAChRs in AD.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M502406200