Article date: September 2012
By: DIC Scopes, E O'Hare, R Jeggo, AD Whyment, D Spanswick, E‐M Kim, J Gannon, H Amijee, JM Treherne in Volume 167, Issue 2, pages 383-392
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.
DOI: 10.1111/j.1476-5381.2012.01973.x
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