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Aβ oligomer toxicity inhibitor protects memory in models of synaptic toxicity
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Scopes, D. I. C., O'Hare, E., Jeggo, R., Whyment, A. D., Spanswick, David, Kim, E. -M., Gannon, J., Amijee, H. and Treherne, J. M. (2012) Aβ oligomer toxicity inhibitor protects memory in models of synaptic toxicity. British Journal of Pharmacology, Volume 167 (Number 2). pp. 383-392. doi:10.1111/j.1476-5381.2012.01973.x ISSN 1476-5381.
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Official URL: http://dx.doi.org/10.1111/j.1476-5381.2012.01973.x
Abstract
BACKGROUND AND PURPOSE
Amyloid-β (Aβ) aggregation into synaptotoxic, prefibrillar oligomers is a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The pharmacological and neuroprotective properties of a novel Aβ aggregation inhibitor, SEN1269, were investigated on aggregation and cell viability and in test systems relevant to synaptic function and memory, using both synthetic Aβ1-42 and cell-derived Aβ oligomers.
EXPERIMENTAL APPROACH
Surface plasmon resonance studies measured binding of SEN1269 to Aβ1–42. Thioflavin-T fluorescence and MTT assays were used to measure its ability to block Aβ1–42–induced aggregation and reduction in cell viability. In vitro and in vivo long-term potentiation (LTP) experiments measured the effect of SEN1269 on deficits induced by synthetic Aβ1–42 and cell-derived Aβ oligomers. Following i.c.v. administration of the latter, a complex (alternating-lever cyclic ratio) schedule of operant responding measured effects on memory in freely moving rats.
KEY RESULTS
SEN1269 demonstrated direct binding to monomeric Aβ1–42, produced a concentration-related blockade of Aβ1–42 aggregation and protected neuronal cell lines exposed to Aβ1–42. In vitro, SEN1269 alleviated deficits in hippocampal LTP induced by Aβ1–42 and cell-derived Aβ oligomers. In vivo, SEN1269 reduced the deficits in LTP and memory induced by i.c.v. administration of cell-derived Aβ oligomers.
CONCLUSIONS AND IMPLICATIONS
SEN1269 protected cells exposed to Aβ1–42, displayed central activity with respect to reducing Aβ-induced neurotoxicity and was neuroprotective in electrophysiological and behavioural models of memory relevant to Aβ-induced neurodegeneration. It represents a promising lead for designing inhibitors of Aβ-mediated synaptic toxicity as potential neuroprotective agents for treating AD.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Journal or Publication Title: | British Journal of Pharmacology | ||||
| Publisher: | John Wiley & Sons Ltd. | ||||
| ISSN: | 1476-5381 | ||||
| Official Date: | 2012 | ||||
| Dates: |
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| Volume: | Volume 167 | ||||
| Number: | Number 2 | ||||
| Page Range: | pp. 383-392 | ||||
| DOI: | 10.1111/j.1476-5381.2012.01973.x | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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