The Identification and Characterization of Excitotoxic Nerve-endings in Alzheimer Disease
Rudi K. Tannenberg, Heather L. Scott, Robert I. Westphalen and Peter R. Dodd
Affiliation: Department ofBiochemistry, University of Queensland, Brisbane 4072, Australia
Keywords: Excitatory Amino Acids, Neurotoxicity, Cerebral Cortex, Glutamate - Receptors, Glutamate - Transporters, Synaptic Terminals, Neurodegenerative Diseases
Regionally specific neuronal loss is a distinguishing feature of Alzheimer disease (AD). Excitotoxicity is a mechanism commonly invoked to explain this. We review the accumulating evidence for such a hypothesis, particularly the altered expression and pharmacology of glutamate receptors and transporters in pathologically susceptible regions of the AD brain. Loss of neurons would be expected to lead to the retrograde degeneration of their afferents, which should be reflected in a loss of presynaptic markers such as synaptophysin. We discuss the possibility that neurons may be destroyed locally, but that glutamatergic presynaptic terminals may remain, or even re-proliferate. The reduced glutamate uptake site density in AD brain may signify a loss of the transporters on otherwise intact terminals, rather than the loss of glutamatergic afferents. Neuronal death may follow if cells are exposed to excessive amounts of glutamate; the loss of transporters from functioning, but defective, glutamate termin als would mean they could continue to release glutamate to exacerbate excitotoxicity. We discuss experimental methods to quantitate synapses, which are crucial for deciding between the various possibilities.
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