Concommitant loss of acetylcholine and somatostatin in the brain during Alzheimer's Disease suggests a functional relationship between this neurotransmitter and peptide. Because acetylcholine and somatostatin are not co-localized to the same cells, receptor-mediated interactions between the two are implied. The cholinergic systems involved are muscarinic and two biochemical processes have been linked to these receptors - increased phosphoinositide turnover and inhibition of adenylate cyclase. Somatostatin analogs are available which can differentiate two types of binding sites on brain membranes, although biochemical correlates of each have not yet been identified. Somatostatin could modulate phosphoinositide metabolism by determining the phosphorylated state of B-50, known to be a regulatory factor in phosphoinositide metabolism. Previous work has suggested that somatostatin acts on B-50 phosphatase and detailed characterization of this enzyme is proposed, since it may be biochemically coupled to a somatostatin receptor. Somatostatin also inhibits adenylate cyclase in several systems. This research will determine whether acetylcholine and somatostatin interact at the level of phosphoinositide/phosphoprotein metabolism or endogenous adenylate cyclase of synaptic membranes. Hippocampal synaptosomes will be prepared, prelabeled with 32 Pi and then incubated with acetylcholine, somatostatin, or both followed by analysis of the 32 P-labeling of phosphoinositide fractions and the protein B-50. Modification of basal and stimulated adenylate cyclase by acetylcholine and somatostatin will be correlated with release of acetylcholine from synaptosomes prelabeled from (3H)- choline. A series of acetylcholine agonists and the selective antagonist pirenzepine will be employed to define the pharmacological specificity of cholinergic responses. Use of analogs known to differentially associate with the two classes of somatostatin receptor in brain membranes will determine which neurochemical systems are linked to each. These studies combine biochemical and pharmacological approaches to define the interaction of acetylcholine and somatostatin with regard to receptor subtypes involved and synaptic compartmentalization. Results so obtained are relevant to the most characteristic neurochemical alterations seen in Alzheimer's Disease. Design of effective therapeutic agents for Alzheimer's Disease will depend on a full definition of the synaptic mechanisms mediated by acetylcholine and somatostatin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023598-03
Application #
3407292
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1987-07-01
Project End
1990-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Toledo
Department
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
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