The long term goal of this research is to investigate age-related changes in the concentrations of excitatory amino acids and in the number and/or affinities of receptors which utilize them as putative neurotransmitters. The process of aging involves a loss of degeneration of neurons and their processes in certain vulnerable brain areas. These pathologic changes are also seen in Alzheimer's disease. However, the severity of degeneration and the extent of brain areas affected are much greater with Alzheimer's disease. Excitatory amino acids have been shown to act as neurotoxins when in excess, such as in hypoxic episodes. They have also been implicated as neurotransmitters of axons which are presynaptic to cholinergic neurons located in areas most affected by aging pathology. The following proposal is based on the hypothesis that excitatory amino acids may act as neurotoxins in the aging process. The proposed investigation is described by the following five specific aims: 1) To determine age-related changes in excitatory amino acid concentration in whole brain and in brain extracellular fluid using HPLC techniques. 2) To analyze the distribution of neurons utilizing glutamate of aspartate within the nucleus basalis, hippocampus and cerebral cortex utilizing monoclonal antibodies and immunohistochemistry. 3) To ascertain the origin of glutamatergic or aspartatergic input to age-affected brain regions using combined retrograde transport-immunohistochemical techniques. 4) To determine possible age-related changes in the number and/or affinity of glutamate receptor binding sites using in vitro receptor autoradiographic techniques. 5) To detemine age-related changes in whole brain concentrations of amino acids and possibly in glutamate binding sites in human autopsy tissue. The results obtained will provide data concerning possible changes in concentrations of excitatory amino acids and their receptors during aging and basic information on the distribution and projections of excitatory amino acid neurons in cerebral cortex, hippocampus and nucleus basalis.
