A beta oligomer toxicity inhibitor protects memory in models of synaptic toxicity

作者：Scopes D I C^*; O' Hare E; Jeggo R; Whyment A D; Spanswick D; Kim E M; Gannon J; Amijee H; Treherne J M

来源：British Journal of Pharmacology, 2012, 167(2): 383-392.

DOI：10.1111/j.1476-5381.2012.01973.x

• Alzheimer%26apos
• s disease
• aggregated A ss
• A ss oligomers
• long-term potentiation
• memory
• pharmacotherapy
• synaptic toxicity

BACKGROUND AND PURPOSE Amyloid-beta (A beta) aggregation into synaptotoxic, prefibrillar oligomers is a major pathogenic event underlying the neuropathology of Alzheimer%26apos;s disease (AD). The pharmacological and neuroprotective properties of a novel A beta aggregation inhibitor, SEN1269, were investigated on aggregation and cell viability and in test systems relevant to synaptic function and memory, using both synthetic A beta 1-42 and cell-derived A beta oligomers. EXPERIMENTAL APPROACH Surface plasmon resonance studies measured binding of SEN1269 to A beta 142. Thioflavin-T fluorescence and MTT assays were used to measure its ability to block A beta 142induced 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 beta 142 and cell-derived A beta 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 beta 142, produced a concentration-related blockade of A beta 142 aggregation and protected neuronal cell lines exposed to A beta 142. In vitro, SEN1269 alleviated deficits in hippocampal LTP induced by A beta 142 and cell-derived A beta oligomers. In vivo, SEN1269 reduced the deficits in LTP and memory induced by i.c.v. administration of cell-derived A beta oligomers. CONCLUSIONS AND IMPLICATIONS SEN1269 protected cells exposed to A beta 142, displayed central activity with respect to reducing A beta-induced neurotoxicity and was neuroprotective in electrophysiological and behavioural models of memory relevant to A beta-induced neurodegeneration. It represents a promising lead for designing inhibitors of A beta-mediated synaptic toxicity as potential neuroprotective agents for treating AD.

• 出版日期2012-9