Recently, a family of five muscarinic acetylcholine receptor genes was identified. The encoded receptors are novel targets for more specific and effective cholinergic therapies for individuals with Alzheimer's disease (AD), but, because of their pharmacological similarities, functions of the subtypes are not well defined. The abundance and localization of individual receptor proteins in the brain, their regulation by cholinergic input, and their involvement in AD have never been studied. In the proposed investigations, subtype-specific polyclonal antisera will be used to evaluate the five native muscarinic receptor proteins in control rat and human brain as well as alterations in receptors in a model of experimental cholinergic deafferentation and in cases of AD. By immunoprecipitation, the relative abundance of proteins will be determined in basal forebrain, neocortex, and hippocampus in rats. By immunocytochemistry, the proteins will be precisely localized and colocalized with cholinergic forebrain neurons. The assessment of receptor number and localization after lesioning of the fimbria-fornix and basal forebrain in rats will provide infomation about the pre- and postsynaptic localization of the subtypes and the cellular and molecular bases for changes induced by deafferentation. Lastly, muscarinic receptor proteins in human brain will be identified, and changes that occur in cases of AD compared to age- and postmortem-matched controls will be measured. These studies will identify the best targets for subtype-specific cholinergic drugs and will provide new neurochemical markers for selective populations of neurons that are potentially at risk in AD.
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