Nicotinic acetylcholine receptors (nAChR) are ACh-gated cation channels. They are widely distributed on neurons and glial cells in the central nervous system, where they are found at postsynaptic locations of cholinergic nerve endings and also at pre-synaptic and peri-synaptic locations of many non-cholinergic neurons. When located in presynaptic endings of neurons, such nAChRs are involved in the regulation of neurotransmitter release, e.g. glutamate, GABA, dopamine, noradrenalin and serotonin. Nicotinic receptors are also expressed on glial cells.
In addition to their roles in neurotransmission, nicotinic recptors by way of their Ca2+ conductivity are often coupled to Ca2+ homeostasis of brain cells and intracellular signalling cascades, making them versatile control elements of synaptic and cellular plasticity. The Ca2+ permeating nAChR α7 subtype seems to be the most important nicotinic receptor for the regulation of plasticity. It has low affinity for the natural transmitters ACh and also is activated by choline, thereby capable of responding to longer lasting tonic changes of ACh and choline levels.
While all nicotinic receptors are ACh-gated cation channels, the various subtypes differ in their ligand binding affinities, and in their cation selectivities, permeabilities and channel kinetics. For example, the α7 nAChR has a relatively low affinity for agonists such as nicotine, and has high Ca2+ permeability, and rapid channel desensitisation. The α4ß2 subtype has relatively high affinity for nicotine and preferentially fluxes Na+ and K+, it also desensitises more slowly. The functional significance of the various subtypes and their differential distribution in the brain is not yet fully understood.
The α7 nAChR seems to play an important role in the plasticity of the central nervous system and in intracellular regulation of a variety of processes, including glucose uptake, energy metabolism and apoptosis. The link between nicotinic receptors and reduced glucose uptake has led to the suggestion that AD may be a neuro-endocrine disorder, resembling a unique form of diabetes mellitus and progressing with accompanied neuro-degeneration. Recently, nicotinic receptors have been shown to be involved in the regulation of cell survival and programmed cell death.
In AD there is a noticable loss of nicotinic recptors correlating with the severity of dementia at the time of death (when the amount of nicotinic receptors can be determined in brain autopsies). Nicotinic APL are capable of enhancing the activity of remaining nicotinic receptors and thereby can ameliorate on the functional level the nicotinic deficit in AD.