Nicotinic acetylcholine receptors (nAChRs) have been pursued for decades as potential molecular targets
to treat cognitive dysfunction in Alzheimer’s disease (AD) due to their positioning within regions of the brain
critical in learning and memory, such as the prefrontal cortex and hippocampus, and their demonstrated role in
processes underlying cognition such as synaptic facilitation, and theta and gamma wave activity. Historically, activity
at these receptors is facilitated in AD by use of drugs that increase the levels of their endogenous agonist acetylcholine,
and more recently nAChR selective ligands have undergone clinical trials. Here we discuss recent findings
suggesting that the expression and function of nAChRs in AD may be regulated by direct interactions with
specific proteins, including Lynx proteins, NMDA-receptors and the Wnt/β-catenin pathway, as well as β-amyloid.
The ability of protein interactions to modify nAChR function adds a new level of complexity to cholinergic signaling
in the brain that may be specifically altered in AD. It is currently not known to what degree current nAChR ligands affect these interactions,
and it is possible that the difference in the clinical effect of nAChR ligands in AD is related to differences in their ability to
modulate nAChR protein interactions, rather than their effects on ion flow through the receptors. Drugs designed to target these interactions
may thus provide a new avenue for drug development to ameliorate cognitive symptoms in AD. Notably, the development of experimental
drugs that specifically modulate these interactions may provide the opportunity to selectively affect those aspects of nAChR
function that are affected in AD.
Keywords: Lynx, Ly-6/uPAR, nicotine, NMDA, Wnt, β-catenin, cognition, amyloid.
Rights & PermissionsPrintExport