The goals of the proposed studies are to examine the roles of specific muscarinic acetylcholine receptor (mAChR) subtypes in signaling in the cortex and hippocampus and to evaluate mechanisms by which mAChE signaling may be disrupted in Alzheimer's disease (AD). Muscarinic cholinergic transmission is important in learning, memory and attention, and defects in cholinergic signaling may contribute to cognitive dysfunction in AD. Five mAChR subtypes (m1-m5), encoded by distinct genes are potentially valuable targets for new cholinergic therapies. However, the roles of m1-m5 are poorly understood because previously available pharmacological tools could not distinguish between them. Here we capitalize on the recent development of mAChR subtype-specific toxins, pharmacological agents, and mice in which the mAChR genes have been disrupted, and propose the following goals: 1) to clarify the signaling specificity of the individual mAChR subtypes in cortical and hippocampal brain slices; 2) to delineate the mAChR subtypes that regulate secretion of amyloid precursor protein (APP) derivatives in cortex and hippocampus; and (3) to test the hypothesis that mAChR trafficking in cell lines is disrupted by presenilin mutations and extracellular Abeta. These studies will provide important insights into the roles of the molecularly distinct mAChR subtypes in basic signaling in cortex and hippocampus, and how they may relate to AD pathogenesis, including regulation of APP secretion and altered membrane protein trafficking. Moreover, the results will help to clarify the potential value of the mAChR subtypes as targets for new pharmacological therapies for AD.
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