title: Glutamate receptors in preclinical research on Alzheimer's disease: update on recent advances.
abstract: 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 ß-protein (Aß) 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 Aß 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. Aß exerts direct and indirect effects on synaptic plasticity-related glutamate receptor signaling and trafficking between different neuronal compartments. For example, Aß-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 Aß have been found to be dependent on endogenous tau located in dendrites or spines. Given the role of glutamatergic transmission in regulating Aß production and release, future therapies targeting glutamate offer the opportunity to remedy both mis-processing of Aß and cellular mechanisms of synaptic failure in early AD.
authors.affiliation: Department of Pharmacology and Therapeutics, Biotechnology Building, Trinity College, Dublin 2, Ireland.
authors.forename: Neng-Wei
authors.initials: NW
authors.lastname: Hu
authors.forename: Tomas
authors.initials: T
authors.lastname: Ondrejcak
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rowan
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D006801:Humans; D017470:Receptors, Glutamate / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D017470:Receptors, Glutamate