There is growing evidence that mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Aβ (amyloid β-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Aβ oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for Aβ, the αv integrin extracellular cell matrix-binding protein and the cytokine TNFα (tumour necrosis factor α) type-1 death receptor mediate Aβ oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNFα or genetic knockout of TNF-R1s (type-1 TNFα receptors) prevented Aβ-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to αv-containing integrins abrogated LTP block by Aβ. Protection against the synaptic plasticity-disruptive effects of soluble Aβ was also achieved using systemically administered small molecules targeting these mechanisms in vivo. Taken together, this research lends support to therapeutic trials of drugs antagonizing synaptic plasticity-disrupting actions of Aβ oligomers in preclinical AD.
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November 2007
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Conference Article|
October 25 2007
Synaptic memory mechanisms: Alzheimer's disease amyloid β-peptide-induced dysfunction
M.J. Rowan;
M.J. Rowan
1
*Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland
†Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland
1To whom correspondence should be addressed (email [email protected]).
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I. Klyubin;
I. Klyubin
†Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland
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Q. Wang;
Q. Wang
‡Department of Physiology, Trinity College, Dublin 2, Ireland
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N.W. Hu;
N.W. Hu
†Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland
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R. Anwyl
R. Anwyl
*Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland
‡Department of Physiology, Trinity College, Dublin 2, Ireland
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Publisher: Portland Press Ltd
Received:
June 13 2007
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2007 Biochemical Society
2007
Biochem Soc Trans (2007) 35 (5): 1219–1223.
Article history
Received:
June 13 2007
Citation
M.J. Rowan, I. Klyubin, Q. Wang, N.W. Hu, R. Anwyl; Synaptic memory mechanisms: Alzheimer's disease amyloid β-peptide-induced dysfunction. Biochem Soc Trans 1 November 2007; 35 (5): 1219–1223. doi: https://doi.org/10.1042/BST0351219
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