alpha 4 but not alpha 3 and alpha 7 nicotinic acetylcholine receptor subunits are lost from the temporal cortex in Alzheimer' s disease

Neuronal nicotinic acetylcholine receptors labelled with tritiated agonists are reduced in the cerebral cortex in Alzheimer's disease (AD), but to dat e it has not been demonstrated which nicotinic receptor subunits contribute to this deficit. In the present study, autopsy tissue from the temporal co rtex of 14 AD cases and 15 age-matched control subjects was compared using immunoblotting with antibodies against recombinant peptides specific for al pha 3, alpha 4, and alpha 7 subunits, in conjunction with [H-3]epibatidine binding. Antibodies to alpha 3, alpha 4, and alpha 7 produced one major ban d on western blots at 59, 51, and 57 kDa, respectively. [H-3]Epibatidine bi nding and alpha 4-like immunoreactivity (using antibodies against the extra cellular domain and cytoplasmic loop of the alpha 4 subunit) were reduced i n AD cases compared with control subjects (p < 0.02) and with a subgroup of control subjects (n = 9) who did not smoke prior to death (p < 0.05) for t he former two parameters, [H-3]Epibatidine binding and cytoplasmic alpha 4- like immunoreactivity were significantly elevated in a subgroup of control subjects (n = 4) known to have smoked prior to death (p < 0.05). There were no significant changes in alpha 3- or alpha 7-like immunoreactivity associ ated with AD or tobacco use. The selective involvement of alpha 4 has impli cations for understanding the role of nicotinic receptors in AD and potenti al therapeutic targets.