Aβ oligomer toxicity inhibitor protects memory in models of synaptic toxicity

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. © 2012 The Authors. British Journal of Pharmacology.