This project is designed to study the cholinergic system in the blood of patients with Alzheimer's Disease and in the brain of a rat model of the disease, aluminum poisoning. There have been brief reports of changes in the erythrocyte choline levels, erythrocyte choline transport, erythrocyte acetylcholinesterase activity and plasma acetylcholinesterase pseudocholinesterase activities in patients with Alzheimer's Disease. The present study will be unique in that we will make all of these measurements in each sample. Subjects will be well documented cases from University Hospital and will consist of controls, aged non-demented, and demented with and without the diagnosis of Alzheimer's Disease. These results should indicate the specificity and degree of biochemical changes occurring in the blood of patients with Alzheimer's Disease. We will examine the data for relationship among the biochemical measures and between biochemical and clinical data. Patients will be re-examined and blood samples obtained at least yearly to investigate the effects of the progressive deterioration of Alzheimer's Disease on these biochemical measures. Confirmation of preliminary evidence of changes in these blood samples will be followed by investigations of possible biochemical mechanisms causing the changes. Among these studies will be measurements of the kinetics of cholinesterase, ion requirements of choline transport, choline transport in erythrocyte ghosts and in """"""""young"""""""" and """"""""old"""""""" fractions of erythrocytes. We will also examine the effects of aluminum on cholinergic activity rat brain because aluminum has been implicated as a causative factor in Alzheimer's Disease. We will test this proposal by treating rats acutely and chronically with aluminum followed by measurements of 14C-glucose conversion to 14C02, 14C-acetylcholine and 14C-lipids in brain slices, high affinity choline transport in synaptosomes, choline acetyltransferase, muscarinic receptors and phosphatidylinositol turnover. We will emphasize measurements that indicate the dynamics of the cholinergic system, such as phosphatidylinositol turnover, choline uptake and acetylcholine synthesis and release. We will also test the effects of drugs that alter cholinergic activity on aluminum toxicity. These experiments should clarify whether or not aluminum causes deficits in the cholinergic system similar to those reported in patients with Alzheimer's Disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG004719-02
Application #
3115291
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-01-01
Project End
1987-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
School of Medicine & Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Connor, D J; Harrell, L E; Jope, R S (1989) Reversal of an aluminum-induced behavioral deficit by administration of deferoxamine. Behav Neurosci 103:779-83
Johnson, G V; Jope, R S (1988) Phosphorylation of rat brain cytoskeletal proteins is increased after orally administered aluminum. Brain Res 456:95-103
Jope, R S (1988) Modulation of phosphoinositide hydrolysis by NaF and aluminum in rat cortical slices. J Neurochem 51:1731-6
Connor, D J; Jope, R S; Harrell, L E (1988) Chronic, oral aluminum administration to rats: cognition and cholinergic parameters. Pharmacol Biochem Behav 31:467-74
Jope, R S; Lally, K M (1988) Synaptosomal calcium influx is activated by sodium fluoride. Biochem Biophys Res Commun 151:774-80
Johnson, G V (1988) The effects of aluminum on agonist-induced alterations in cyclic AMP and cyclic GMP concentrations in rat brain regions in vivo. Toxicology 51:299-308
Johnson, G V; Simonato, M; Jope, R S (1988) Dose- and time-dependent hippocampal cholinergic lesions induced by ethylcholine mustard aziridinium ion: effects of nerve growth factor, GM1 ganglioside, and vitamin E. Neurochem Res 13:685-92
Koenig, M L; Jope, R S (1987) Aluminum inhibits the fast phase of voltage-dependent calcium influx into synaptosomes. J Neurochem 49:316-20
Jope, R S; Casebolt, T L; Johnson, G V (1987) Modulation of carbachol-stimulated inositol phospholipid hydrolysis in rat cerebral cortex. Neurochem Res 12:693-700
Johnson, G V; Jope, R S (1987) Aluminum alters cyclic AMP and cyclic GMP levels but not presynaptic cholinergic markers in rat brain in vivo. Brain Res 403:1-6

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