Alzheimer's disease (AD) is characterized by brain accumulation of the 
neurotoxic amyloid-β peptide (Aβ) 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 Aβ than with the extent of amyloid plaque deposits in affected brains. 
Inhibition of nAChRs by soluble Aβ40 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 Aβ40 and blocking Aβ-induced inhibition of 
carbamylcholine-induced currents in PC12 cells expressing α7 nAChRs. Using 
alanine scanning mutagenesis and whole-cell current recording, we have now 
defined the amino acids in IQ essential for reversal of Aβ40 inhibition of 
carbamylcholine-induced responses in PC12 cells, mediated by α7 subtypes and 
other endogenously expressed nAChRs. We further investigated the effects of 
soluble Aβ, IQ and analogues of IQ on α3β4 nAChRs recombinantly expressed in 
HEK293 cells. Results show that nanomolar concentrations of soluble Aβ40 
potently inhibit the function of α3β4 nAChRs, and that subsequent addition of IQ 
or its analogues does not reverse this effect. However, co-application of IQ 
makes the inhibition of α3β4 nAChRs by Aβ40 reversible. These findings indicate 
that Aβ40 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.