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.
Showing the most recent 10 out of 13 publications
