Glutamate Receptors and Excitotoxic Mechanisms in Alzheimer’s Disease

Abstract

Large pyramidal neurons, the neurons most vulnerable in Alzheimer’s disease (AD), use glutamate as a neurotransmitter and receive glutamatergic inputs (Fonnum, 1984; Hof and Morrison, 1994). Loss of these neurons would be expected to result in decreased glutamate levels, loss of glutamate receptors, and loss of presynaptic glutamate transport sites. Of potentially greater interest is the possibility that glutamate may play a causal role in AD neuropathology. Glutamate and its receptors play critical roles in long-term potentiation—a cellular model of learning and memory (Asztely and Gustafsson, 1996; Riedel and Reymann, 1996)—and in spatial memory (Morris et al., 1986), thus glutamate receptor dysfunction could contribute to the memory deficits evident in AD. Overstimulation of glutamate receptors can result in neuron death through excitotoxic mechanisms (Choi, 1992). Moreover, glutamate can cause cytoskeletal disruption resembling that associated with neurofibrillary pathology in AD (De Boni and McLachlan, 1985; Mattson, 1990; Couratier et al., 1996). In this chapter the evidence of disrupted glutamatergic transmission in Alzheimer’s disease is reviewed, and the possibility that it may contribute to, or result from, the disease process is discussed.