Acidic amino acids (EAAs) such as glutamate are the most abundant excitatory neurotransmitters within the mammalian central nervous system and play a major role in behavioral processes such as learning and memory.
The aim of this project is to investigate how EAA receptor genes and gene products are expressed In the primate brain, especially in those areas that show profound neuronal loss in patients affected with Alzheimer's disease (i.e. the cerebral cortex and hippocampus). Ongoing studies in our laboratory provided compelling evidence that EAA receptors play a major role in regulating reproductive function and led to the general conclusion that a high level of EAA receptor gene expression offers individuals a selective advantage by enhancing reproductive fitness. We suspect, however, that a high level of EAA receptor gene expression is likely to have deleterious consequences later in life. Specifically, we hypothesize that abnormally high levels of EAA receptor gene expression, especially in the cortex and hippocampus, significantly contribute to the etiology of Alzheimer's (AD) disease by rendering the neurons of these areas especially susceptible to the excitotoxic action of endogenous and exogenous EAAs; this leads to premature neuronal loss together with the development of the irreversible dementia that characterizes AD. To elucidate the role played by EAAs and their receptors in the normal aging process and in the etiology of AD we propose to characterize in detail the changes in glutamatergic mechanisms that arise during the course of normal aging and to compare them to the changes that occur in AD. The following specific research aims are proposed: l) To characterize EAA receptor gene expression within the central nervous system of macaques, during normal aging and after manipulation of the sex-steroid environment. Using in situ hybridization histochemistry and immunocytochemistry, respectively, we will examine the distribution and relative density of the different molecular forms of glutamate receptor mRNA and post-translation products within the cortex and hippocampus. Using brains obtained from rhesus macaques at different stages of aging, and different sex-steroid status (e.g. post-gonadectomy), we expect to demonstrate that as the normal brain ages there is a nonpathological decline in EAA receptor gene expression within the cortex and hippocampus and that this decline is to a large extent the result of declining sex-steroid production. 2) To characterize EAA receptor gene expression within the central nervous system of normal aged humans and those showing AD. In situ hybridization histochemistry and immunocytochemistry, respectively, will be used to examine the distribution and relative density of the different molecular forms of glutamate receptor mRNA and post-translation products in the brains of AD individuals and age-matched non-demented controls. It is predicted that the cortex and hippocampus of AD individuals will show extremely high levels of EAA receptor gene expression. Furthermore, the local areas showing the most concentrated expression are expected to be associated most strongly with neuronal loss and amyloid plaque deposition. The results are expected to significantly further our understanding of the excitotoxic properties of EAAs and to shed light on how they may contribute to the etiology of cognitive deficits associated with AD. Moreover, they should also help to lay a foundation for possible approaches to the effective therapy of AD.
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