| Aβ oligomer toxicity inhibitor protects memory in models of synaptic toxicity. | |
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MedLine Citation:
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PMID: 22913627 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 Aβ(1-42) and cell-derived Aβ oligomers. EXPERIMENTAL APPROACH: Surface plasmon resonance studies measured binding of SEN1269 to Aβ(1-42) . Thioflavin-T fluorescence and MTT assays were used to measure its ability to block Aβ(1-42) -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 Aβ(1-42) 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 Aβ(1-42) , produced a concentration-related blockade of Aβ(1-42) aggregation and protected neuronal cell lines exposed to Aβ(1-42) . In vitro, SEN1269 alleviated deficits in hippocampal LTP induced by Aβ(1-42) 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 Aβ(1-42) , 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. |
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Authors:
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D I C Scopes; E O'Hare; R Jeggo; A D Whyment; D Spanswick; E-M Kim; J Gannon; H Amijee; J M Treherne |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: British journal of pharmacology Volume: 167 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2012 Sep |
Date Detail:
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Created Date: 2012-08-23 Completed Date: 2013-01-07 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 383-92 Citation Subset: IM |
Copyright Information:
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© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society. |
Affiliation:
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Senexis Limited, Babraham Research Campus, Cambridge, UK. david_scopes@senexis.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aminophenols
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pharmacology* Amyloid beta-Peptides / toxicity* Animals Cell Line Diamines / chemistry, pharmacology* Immobilized Proteins / chemistry, metabolism Male Memory / drug effects Molecular Structure Protein Binding Pyridazines / chemistry, pharmacology* Pyrimidines / pharmacology* Rats Rats, Sprague-Dawley Synapses / drug effects* |
| Grant Support | |
ID/Acronym/Agency:
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//Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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0/Aminophenols; 0/Amyloid beta-Peptides; 0/Diamines; 0/Immobilized Proteins; 0/N,N'-bis(3-hydroxyphenyl)pyridazine-3,6-diamine; 0/Pyridazines; 0/Pyrimidines; 0/SEN1269 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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