Acetylcholine Muscarinic M2 Receptor Stimulated [35S]GTPγS Binding Shows Regional Selective Changes in Alzheimer's Disease Postmortem Brain

Oxotremorine-M stimulated [³⁵S]GTPγS binding was used to assess acetylcholine muscarinic M2 receptor mediated G-protein function in superior frontal cortical, superior temporal cortical and hippocampal membranes from a series of Alzheimer's disease and matched control subjects. No significant differences were seen in basal [³⁵S]GTPγS binding between the groups. The maximal level of oxotremorine-M stimulated [³⁵S]GTPγS binding over basal was significantly increased in Alzheimer's disease superior temporal cortex, suggesting an enhanced muscarinic M2 receptor-G-protein coupling efficiency in this region. In contrast, the maximal level of oxotremorine-M stimulated [³⁵S]GTPγS binding over basal was unaltered in Alzheimer's disease superior frontal cortex and significantly reduced in Alzheimer's disease hippocampus. Western immunoblotting using antisera towards the α-subunits of those G-protein types known to couple muscarinic receptors, revealed that G_qαand G_iα, but not G_oα, levels were significantly reduced in Alzheimer's disease superior temporal cortex. Neither G_qα, G_iαnor G_oαlevels were significantly altered in Alzheimer's disease superior frontal cortex or hippocampus. These results suggest that the efficacy of muscarinic M₂receptor G-protein coupling shows regional selective changes in Alzheimer's disease postmortem brain with deficits occurring only in a region that shows severe pathology.