The neurochemical pathology of Alzheimer's disease, the most common cause of dementia, has received increasingly more attention in the last decade. Work from neurotransmitter systems are pathologically involved in this neurodegenerative disorder. Neurons affected include cholinergic neurons in the basal forebrain, and two groups of neuropeptide-containing cells: somatostatin neurons in the cerebral cortex and other brain areas, and CRF-containing cells in the cerebral cortex and striatum. Other peptidergic neurons such as those containing cholecystokinin, vasopressin and vasoactive-intestinal peptide apparently spared. In the present competitive renewal application we seek to scrutinize in detail, the dynamic state of the 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), receptor number and affinity, and receptor occupancy (Rb+ flux), the dynamic state of cholinergic neurotransmission will be assessed in several brain regions from histologically- confirmed Alzheimer's disease and age- and sex-matched controls. Such experiments will probably provide the mechanism(s) by which choline and lecithin therapy are ineffective in Alzheimer's disease. In addition, we shall continue our work on peptidergic (SRIF, CRF, and others) systems in Alzheimer's disease including a detailed mapping of the pathological involvement of CRF- and SRIF containing neurons in the Alzheimer's disease by measurement of the concentrations of those peptides in more than 30 brain areas. Moreover, SRIF and CRF receptor binding will be assessed, as will functional responses of these receptors, i.e. cyclic AMP production and phosphoinositide hydrolysis. The majority of these studies are feasible because of the unique availability of the rapid autopsy tissue - our research group is the only in the world conducting this procedure. These studies will provide novel data that should result in the development of a rational drug therapy in patients with Alzheimer's disease. Finally the measurement of several neuropeptides in cerebrospinal fluid of patients with Alzheimer's disease, patients with other neuropsychiatric disorders and controls may provide a diagnostic test for this disorder.
Showing the most recent 10 out of 43 publications
