Mechanisms of the inhibitory effects of amyloid beta-protein on synaptic plasticity.
Alzheimer's disease can be considered a protein misfolding disease. In particular, inappropriate processing of a proteolytic fragment of amyloid precursor protein, amyloid beta-protein (Abeta), in early stages of Alzheimer's disease may lead to stabilization of small oligomers that are highly mobile and have a potential to be extremely toxic assemblies. Recently, the importance of such soluble species of Abeta in triggering synaptic dysfunction, long before neuronal loss occurs, has become apparent. Animal models have revealed that plasticity of hippocampal excitatory synaptic transmission is relatively selectively vulnerable to Abeta both in vitro and in vivo. This review focuses on the mechanisms of Abeta inhibition of long-term potentiation at synapses in the rodent hippocampus from two complimentary perspectives. Firstly, we examine evidence that the synaptic activity of this peptide resides primarily in oligomeric rather than monomeric or fibrillar Abeta species. Secondly, the importance of different oxidative/nitrosative stress-linked cascades including JNK, p38 MAPK and NADPH oxidase/iNOS-generated reactive oxygen/nitrogen free radicals in mediating the inhibition of LTP by Abeta is emphasised. These mechanistic studies provide a plausible explanation for the sensitivity of hippocampus-dependent memory to impairment in the early preclinical stages of Alzheimer's disease.
Rowan
Michael J
MJ
Trinity College Institute of Neuroscience, Department of Pharmacology and Therapeutics, Trinity College, Biotechnology Building, Dublin 2, Ireland. mrowan@tcd.ie
Klyubin
Igor
I
Wang
Qinwen
Q
Anwyl
Roger
R
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018450:Disease Progression; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects; D023421:Models, Animal; D009154:Mutation; D009473:Neuronal Plasticity / Q000187:drug effects*; D018384:Oxidative Stress; D051381:Rats
D016229:Amyloid beta-Peptides