Aβ oligomer toxicity inhibitor protects memory in models of synaptic toxicity

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.