| Autor: |
Selkoe, Dennis J., Triller, Antoine, Christen, Yves, Rowan, Michael J., Klyubin, Igor, Cullen, William K., Hu, NengWei, Anwyl, Roger |
| Zdroj: |
Synaptic Plasticity & the Mechanism of Alzheimer's Disease; 2008, p157-167, 11p |
| Abstrakt: |
The mechanisms of the relatively selective vulnerability of plasticity at excitatory synapses to the disruptive actions of Aβ may provide new insights into novel therapies for Alzheimer'sdisease(AD).Wehaveexaminedtheabilityof exogenouslyappliedandendogenously generated Aβ antibodies to prevent Aβ inhibition of long-term potentiation (LTP) in the rat hippocampus in vivo. Cell-derived oligomers of Aβ and human cerebrospinal fluid containing Aβ oligomers rapidly inhibited LTP at extremely low concentrations. Antibodies that bound Aβ oligomers abrogated theAβ-induced disruption of LTP by directly neutralizing them in the brain. Alzheimer's disease pathology is associated with the activation of certain pro-inflammatory oxidative/nitrosative stress-linked cascades and cytokine pathways.We found that the disruption of LTP in vitro by Aβ was prevented by pharmacological inhibition or gene knockout of JNK, p38MAPK, NADPH oxidase, iNOS, TNFα and type 1 TNF receptors. Recently we also found that agents, including antibodies and a small molecule inhibitor, that bound a putative receptor for Aβ, the αv integrin, could prevent the Aβ-induced inhibition of LTP both in vitro and in vivo. Our studies provide a window on likely mechanisms of synaptic plasticity disruption in Alzheimer'sdiseaseandhowtheymaybe successfully targetedusingimmunological andpharmacological means, potentially long before pathological synaptic or neuronal loss occurs. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Supplemental Index |
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