The neurochemical pathology of Alzheimer's disease (AD), the most common cause of dementia, has received increasingly more attention. It is now evident that specific chemically-defined neurotransmitter systems are pathologically involved in this neurodegenerative disorder. Neurons affected include cholinergic neurons in the basal forebrain, GABA-containing neurons and two groups of neuropeptide-containing cells: somatostatin- and CRF-containing cells in the cerebral cortex. Other peptidergic neurons such as those containing cholecystokinin and vasoactive-intestinal peptide are apparently spared. In the present competitive renewal application we seek to continue to scrutinize in detail, the dynamic state of cholinergic neurons using tissue obtained in the Rapid Autopsy Procedure (20-60 min after death). By measuring markers of neuronal integrity, neuronal activity (high affinity choline uptake), the choline transporter itself, receptor number and affinity, and second messenger as well as third messenger responses (protein phosphorylation), the dynamic state of cholinergic neurotransmission will be assessed in several brain regions from histologically-confirmed AD and age- and sex-matched controls. In addition, we shall continue our work on peptidergic (SRIF and CRF) systems in Alzheimer's disease including assessment of the relationship between CSF and brain concentrations of these peptides. Moreover, SRIF receptor subtypes will be measured, as will functional responses of these receptors. We shall also determine the relationship between the presence of the abnormal ADassociated protein, Alz 68, and the alterations in ACh and peptidergic neurons. We shall also scrutinize alterations in GABA-containing neurons in AD. The majority of these studies are feasible because of the unique availability of the rapid autopsy tissue - our center is the only one in the world conducting this procedure. These studies will provide novel data that may well result in the development of a rational drug therapy in patients with AD.
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