We and others have observed significant decreases in the number of glutamate receptors in the cortex and hippocampus of brains of patients with Alzheimer's disease. Other observers have noted significant decreases in presynaptic markers for glutamate terminals in Alzheimer's disease brains. Glutamate is the most abundant excitatory amino acid neurotransmitter in the brain. It is vital to normal brain function, acting through at least 4 different kinds of receptors. However, it is also a potent neurotoxin under certain circumstances. It remains a distinct possibility that glutamate neurotoxicity plays a role in the pathogenesis of Alzheimer's disease. During the first three years of this grant we have been able to confirm and extend our original observation that glutamate receptors are decreased in Alzheimer's disease. We have also been able to develop highly specific, autoradiographic assays for each of the subtypes of glutamate receptors, and to collect a number of brains from patients whose symptoms were well characterized during life. We now propose to use these highly specific assays to examine changes in the different glutamate receptor subtypes in 13 regions from the brains of the well characterized Alzheimer's, non- Alzheimer's dementia and control patients. The glutamate receptor subtype changes will be compared to measures of Alzheimer's pathology: thioflavin-S and Alz-50 staining of the tissue. In this way we expect to more fully understand the relationship between glutamate receptor changes and the symptoms and pathophysiology of Alzheimer's disease.
