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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS030454-10
Application #
2902334
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Murphy, Diane
Project Start
1991-09-30
Project End
2004-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
10
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lebois, Evan P; Schroeder, Jason P; Esparza, Thomas J et al. (2017) Disease-Modifying Effects of M1 Muscarinic Acetylcholine Receptor Activation in an Alzheimer's Disease Mouse Model. ACS Chem Neurosci 8:1177-1187
Davis, Albert A; Heilman, Craig J; Brady, Ashley E et al. (2010) Differential effects of allosteric M(1) muscarinic acetylcholine receptor agonists on receptor activation, arrestin 3 recruitment, and receptor downregulation. ACS Chem Neurosci 1:542-551
Davis, Albert A; Fritz, Jason J; Wess, Jürgen et al. (2010) Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo. J Neurosci 30:4190-6
Shirey, Jana K; Brady, Ashley E; Jones, Paulianda J et al. (2009) A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning. J Neurosci 29:14271-86
Cabadak, Hulya; Cuadra, Adolfo E; El-Fakahany, Esam E et al. (2009) M2, M3, and M4 muscarinic receptors are expressed in the guinea pig gallbladder. J Recept Signal Transduct Res 29:63-6
Bazalakova, M H; Wright, J; Schneble, E J et al. (2007) Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice. Genes Brain Behav 6:411-24
McClatchy, Daniel B; Fang, Guofu; Levey, Allan I (2006) Elongation factor 1A family regulates the recycling of the M4 muscarinic acetylcholine receptor. Neurochem Res 31:975-88
Bernstein, Leah S; Ramineni, Suneela; Hague, Chris et al. (2004) RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11alpha signaling. J Biol Chem 279:21248-56
Li, Bin; Duysen, Ellen G; Volpicelli-Daley, Laura A et al. (2003) Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice. Pharmacol Biochem Behav 74:977-86
Ferguson, Shawn M; Savchenko, Valentina; Apparsundaram, Subbu et al. (2003) Vesicular localization and activity-dependent trafficking of presynaptic choline transporters. J Neurosci 23:9697-709

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