AD (Alzheimer's disease) is characterized by a progressive and devastating mental decline that is usually presaged by impairment of a form of memory dependent on medial temporal lobe structures, including the hippocampus. The severity of clinical dementia correlates positively with the cerebral load of the AD-related protein Aβ (amyloid β), particularly in its soluble form rather than the insoluble fibrillar Aβ found in amyloid plaques. Recent research in animal models of AD has pointed to a potentially important role for rapid disruptive effects of soluble species of Aβ on neural function in causing a relatively selective impairment of memory early in the disease. Our experiments assessing the mechanisms of Aβ inhibition of LTP (long-term potentiation), a correlate of memory-related synaptic plasticity, in the rodent hippocampus showed that low-n oligomers were the soluble Aβ species primarily responsible for the disruption of synaptic plasticity in vivo. Exogenously applied and endogenously generated anti-Aβ antibodies rapidly neutralized and prevented the synaptic plasticity disrupting effects of these very potent Aβ oligomers. This suggests that active or passive immunotherapeutic strategies for early AD should target Aβ oligomers in the brain. The ability of agents that reduce nitrosative/oxidative stress or antagonize stress-activated kinases to prevent Aβ inhibition of LTP in vitro points to a key role of these cellular mechanisms at very early stages in Aβ-induced neuronal dysfunction. A combination of antibody-mediated inactivation of Aβ oligomers and pharmacological prevention of cellular stress mechanisms underlying their synaptic plasticity disrupting effects provides an attractive strategy in the prevention of early AD.
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August 2005
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Conference Article|
August 01 2005
Synaptic plasticity disruption by amyloid β protein: modulation by potential Alzheimer's disease modifying therapies
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 mrowan@tcd.ie).
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I. Klyubin;
I. Klyubin
*Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland
†Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland
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Q. Wang;
Q. Wang
*Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland
‡Department of Physiology, 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:
March 28 2005
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2005 The Biochemical Society
2005
Biochem Soc Trans (2005) 33 (4): 563–567.
Article history
Received:
March 28 2005
Citation
M.J. Rowan, I. Klyubin, Q. Wang, R. Anwyl; Synaptic plasticity disruption by amyloid β protein: modulation by potential Alzheimer's disease modifying therapies. Biochem Soc Trans 1 August 2005; 33 (4): 563–567. doi: https://doi.org/10.1042/BST0330563
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