Glutamate receptors in preclinical research on Alzheimer's disease: Update on recent advances

The cognitive and related symptoms of Alzheimer's disease are mainly attributable to synaptic failure. Here we review recent research on how the Alzheimer's disease amyloid beta-protein (A beta) affects glutamate receptors and fast excitatory synaptic transmission and plasticity of that transmission. L-glutamate. the main excitatory neurotransmitter in the brain, has long been implicated in causing NMDA receptor-mediated excitotoxicity leading to neurodegeneration in the late stages of the disease. However there is now extensive evidence that soluble A beta oligomers disrupt synaptic transmission and especially synaptic plasticity via non-excitotoxic glutamatergic mechanisms. New data highlight the relatively selective involvement of certain glutamate receptor subtypes including GluN2B (NR2B) subunit-containing NMDA receptors and mGlu5 receptors. A beta exerts direct and indirect effects on synaptic plasticity-related glutamate receptor signaling and trafficking between different neuronal compartments. For example, A beta-induced ectopic NMDA and mGlu receptor-mediated signaling coupled with caspase-3 activation may cause inhibition of long-term potentiation and facilitation of long-term depression. Intriguingly, some of the disruptive synaptic actions of A beta have been found to be dependent on endogenous tau located in dendrites or spines. Given the role of glutamatergic transmission in regulating A beta production and release, future therapies targeting glutamate offer the opportunity to remedy both mis-processing of A beta and cellular mechanisms of synaptic failure in early AD. (C) 2011 Elsevier Inc. All rights reserved.