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A? oligomer toxicity inhibitor protects memory in models of synaptic toxicity.
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ABSTRACT: Background and purpose
Amyloid-? (A?) 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 A? aggregation inhibitor, SEN1269, were investigated on aggregation and cell viability and in test systems relevant to synaptic function and memory, using both synthetic A?(1-42) and cell-derived A? oligomers.Experimental approach
Surface plasmon resonance studies measured binding of SEN1269 to A?(1-42) . Thioflavin-T fluorescence and MTT assays were used to measure its ability to block A?(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 A?(1-42) and cell-derived A? 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 A?(1-42) , produced a concentration-related blockade of A?(1-42) aggregation and protected neuronal cell lines exposed to A?(1-42) . In vitro, SEN1269 alleviated deficits in hippocampal LTP induced by A?(1-42) and cell-derived A? oligomers. In vivo, SEN1269 reduced the deficits in LTP and memory induced by i.c.v. administration of cell-derived A? oligomers.Conclusions and implications
SEN1269 protected cells exposed to A?(1-42) , displayed central activity with respect to reducing A?-induced neurotoxicity and was neuroprotective in electrophysiological and behavioural models of memory relevant to A?-induced neurodegeneration. It represents a promising lead for designing inhibitors of A?-mediated synaptic toxicity as potential neuroprotective agents for treating AD.
SUBMITTER: Scopes DI
PROVIDER: S-EPMC3481045 | biostudies-literature | 2012 Sep
REPOSITORIES: biostudies-literature
Publications
Aβ oligomer toxicity inhibitor protects memory in models of synaptic toxicity.
British journal of pharmacology 20120901 2
<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Surface pla ...[more]