Document Detail

Aβ oligomer toxicity inhibitor protects memory in models of synaptic toxicity.
MedLine Citation:
PMID:  22913627     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  167     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-23     Completed Date:  2013-01-07     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  383-92     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Senexis Limited, Babraham Research Campus, Cambridge, UK.
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MeSH Terms
Aminophenols / pharmacology*
Amyloid beta-Peptides / toxicity*
Cell Line
Diamines / chemistry,  pharmacology*
Immobilized Proteins / chemistry,  metabolism
Memory / drug effects
Molecular Structure
Protein Binding
Pyridazines / chemistry,  pharmacology*
Pyrimidines / pharmacology*
Rats, Sprague-Dawley
Synapses / drug effects*
Grant Support
//Wellcome Trust
Reg. No./Substance:
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

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