Peptide blockers of the inhibition of neuronal nicotinic acetylcholine receptors by amyloid beta

Peptide blockers of the inhibition of neuronal nicotinic acetylcholine receptors by amyloid beta

Author Magdesian, M. H. Google Scholar
Nery, A. A. Google Scholar
Martins, Antonio Henrique Baccin Autor UNIFESP Google Scholar
Juliano, Maria Aparecida Autor UNIFESP Google Scholar
Juliano, Luiz Autor UNIFESP Google Scholar
Ulrich, Alexander Henning Autor UNIFESP Google Scholar
Ferreira, Sergio T. Google Scholar
Institution Universidade Federal do Rio de Janeiro (UFRJ)
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Abstract Alzheimer disease ( AD) is characterized by accumulation of the neurotoxic amyloid beta peptide ( A beta) and by the loss of cholinergic neurons and nicotinic acetylcholine receptors ( nAChRs) throughout the brain. Direct inhibition of nAChRs by A beta has also been suggested to contribute to cholinergic dysfunction in AD. in an effort to find ligands capable of blocking A beta- induced inhibition of nAChRs, we have screened a phage display library to identify peptides that bind to A beta. Using this approach, we identified a heptapeptide denoted IQ, which binds with nanomolar affinity to A beta and is homologous to the acetylcholine- binding protein and to most subtypes of nAChRs. Rapid kinetic whole- cell current- recording measurements showed that A beta inhibits nAChR function in a dose- dependent manner in neuronal differentiated PC12 cells and that nanomolar concentrations of IQ completely block the inhibition by A beta. These results indicate that the A beta binding site in nAChRs is homologous to the IQ peptide and that this is a relevant target for A beta neurotoxicity in AD and, more generally, for the regulation of nAChR function by soluble A beta 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.
Language English
Date 2005-09-02
Published in Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 280, n. 35, p. 31085-31090, 2005.
ISSN 0021-9258 (Sherpa/Romeo, impact factor)
Publisher Amer Soc Biochemistry Molecular Biology Inc
Extent 31085-31090
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000231487800053

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