This renewal application focuses on regulation of muscarinic acetylcholine receptors (mAChR) and novel therapeutic approaches to cholinergic involvement in common neuropsychiatric symptoms of human neurological diseases. Cholinesterase inhibitors are the main cholinomimetics available for clinical use, but are only modestly effective and frequently cause adverse effects. Cholinesterase inhibitors act indiscriminately on all members of the mAChR family (M1-M5), but recent evidence suggests that drugs targeted to individual receptor subtypes will be more effective and have fewer side effects. Remarkably, there is also evidence that activation of mAChR subtypes may influence the neuropathology and progression of Alzheimer's disease (AD). The goal of advancing cholinergic therapies through targeting mAChR subtypes has been hampered by several factors, including lack of highly selective drugs, poor understanding of the roles of individual receptors, limited availability of mouse models, and adaptive mechanisms that limit responsiveness during chronic stimulation. However, we and others have made exciting progress overcoming these limitations. This proposal capitalizes on recent progress to test the central hypothesis that activation and antagonism of central M1 receptors play opposing roles in AD.
Three Specific Aims will 1) characterize novel drugs that selectively activate M1, 2) evaluate the effects of non-specific and M1-specific cholinomimetics on amyloidogenesis, and 3) evaluate the role of mAChR subtypes in mediating anticholinergic effects and modulating the progression of AD. In order to achieve these Aims, we will employ a blend of pharmacologic approaches using drugs with distinct actions on mAChR, and genetic approaches using transgenic mouse models of amyloidogenesis and knock out mice deficient in individual mAChR subtypes. The results of these studies should substantially advance the goal of developing more effective cholinergic therapies for AD and other neuropsychiatric disorders.
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