Excitatory amino acids (EAA) are the neurotransmitters of the majority of cortical and hippocampal excitatory pathways in mammalian brain and are the likely neurotransmitters of cortical and hippocampal pyramidal neurons. The pyramidal neurons of association cortex and hippocampus develop neurofibrillary tangles early in AD. Biochemical and anatomical studies of Ad brain show decreases in glutamate levels and EAA receptors. EAA have been hypothesized to play a role in AD because EAA agonists are excitotoxic and because the area most affected in AD have high concentrations of EAA and EAA receptors. Among the three EAA receptors linked to ion channels (the N-methyl-D-aspartate (NMDA), alpha-amino-3- hydroxy-5-methyl-4-isoxazole-4-propionic acid receptor (AMPA) and kainate receptors), the NMDA receptors are decreased to a greater extent than others. Two types of metabotropic EAA receptor exist, one linked to phosphoinositol metabolism which is variably decreased in AD brain and one linked to adenylate cyclase which is markedly decreased in AD. Not all cortical areas with high densities of these markers are affected in AD, however, and thus any role of EAA in the pathogenesis of AD must be secondary to their additional features of neuronal vulnerability. The regional hierarchy of cellular vulnerability to neurofibrillary degeneration has been defined in aging and AD. Furthermore, the genes for the various EAA receptor subtypes have been cloned and specific antibodies to most of them have been produced. It is thus possible to define the relationship of particular EAA receptor subtype genes and proteins to other potential markers of neurodegeneration in AD. In this project, receptor autoradiography, in situ hybridization and immunocytochemistry will be used to address two hypotheses concerning the role of EAA in aging and AD. The first hypothesis is that high densities of NMDA receptors, high densities of MGluR5 receptors and low densities of mGluR1 receptors are expressed in those neurons preferentially lost in aging and AD. The second hypothesis is that high densities of NMDA receptors are expressed in cells with high densities of MPA kinases and APP and APLP and low densities of NMDA receptors are expressed in nitric oxide synthase containing neurons. These studies will be carried out in close collaboration with projects 2,3, and 4 which will independently be examining related aspects of the potential metabolic and excitotoxic cascades involved in the cellular vulnerability of aging and AD. The project will also use the reagent core for tissue acquisition and analysis of EAA receptor proteins and genes by Western and Northern blot analysis.
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