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Title: Rescue of Amyloid-Beta-Induced Inhibition of Nicotinic Acetylcholine Receptors by a Peptide Homologous to the Nicotine Binding Domain of the Alpha 7 Subtype
Authors: Nery, Arthur A.
Magdesian, Margaret H.
Trujillo, Cleber A.
Sathler, Luciana B.
Juliano, Maria A. [UNIFESP]
Juliano, Luiz [UNIFESP]
Ulrich, Henning
Ferreira, Sergio T.
Universidade de São Paulo (USP)
Universidade Federal do Rio de Janeiro (UFRJ)
Universidade Federal de São Paulo (UNIFESP)
Issue Date: 22-Jul-2013
Publisher: Public Library Science
Citation: Plos One. San Francisco: Public Library Science, v. 8, n. 7, 9 p., 2013.
Abstract: Alzheimer's disease (AD) is characterized by brain accumulation of the neurotoxic amyloid-beta peptide (A beta) and by loss of cholinergic neurons and nicotinic acetylcholine receptors (nAChRs). Recent evidence indicates that memory loss and cognitive decline in AD correlate better with the amount of soluble A beta than with the extent of amyloid plaque deposits in affected brains. Inhibition of nAChRs by soluble A beta 40 is suggested to contribute to early cholinergic dysfunction in AD. Using phage display screening, we have previously identified a heptapeptide, termed IQ, homologous to most nAChR subtypes, binding with nanomolar affinity to soluble A beta 40 and blocking A beta-induced inhibition of carbamylcholine-induced currents in PC12 cells expressing alpha 7 nAChRs. Using alanine scanning mutagenesis and whole-cell current recording, we have now defined the amino acids in IQ essential for reversal of A beta 40 inhibition of carbamylcholine-induced responses in PC12 cells, mediated by alpha 7 subtypes and other endogenously expressed nAChRs. We further investigated the effects of soluble A beta, IQ and analogues of IQ on alpha 3 beta 4 nAChRs recombinantly expressed in HEK293 cells. Results show that nanomolar concentrations of soluble A beta 40 potently inhibit the function of alpha 3 beta 4 nAChRs, and that subsequent addition of IQ or its analogues does not reverse this effect. However, co-application of IQ makes the inhibition of alpha 3 beta 4 nAChRs by A beta 40 reversible. These findings indicate that A beta 40 inhibits different subtypes of nAChRs by interacting with specific receptor domains homologous to the IQ peptide, suggesting that IQ may be a lead for novel drugs to block the inhibition of cholinergic function in AD.
ISSN: 1932-6203
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