期刊
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
卷 100, 期 4, 页码 855-862出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbb.2011.04.013
关键词
Dementia; Synaptic plasticity; Long-term potentiation; Long-term depression; L-glutamate receptor trafficking; Learning
资金
- Science Foundation Ireland
- Health Research Board of Ireland
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.
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