Abeta oligomer toxicity inhibitor protects memory in models of synaptic toxicity

D.I.C. Scopes, Eugene O'Hare, R. Jeggo, A.D. Whyment, D. Spanswick, E-M. Kim, J. Gannon, H. Amijee, J.M. Treherne

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Abstract

BACKGROUND AND PURPOSE:

Amyloid-ß (Aß) 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 Aß aggregation inhibitor, SEN1269, were investigated on aggregation and cell viability and in test systems relevant to synaptic function and memory, using both synthetic Aß(1-42) and cell-derived Aß oligomers.
EXPERIMENTAL APPROACH:

Surface plasmon resonance studies measured binding of SEN1269 to Aß(1-42) . Thioflavin-T fluorescence and MTT assays were used to measure its ability to block Aß(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 Aß(1-42) and cell-derived Aß 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 Aß(1-42) , produced a concentration-related blockade of Aß(1-42) aggregation and protected neuronal cell lines exposed to Aß(1-42) . In vitro, SEN1269 alleviated deficits in hippocampal LTP induced by Aß(1-42) and cell-derived Aß oligomers. In vivo, SEN1269 reduced the deficits in LTP and memory induced by i.c.v. administration of cell-derived Aß oligomers.
CONCLUSIONS AND IMPLICATIONS:

SEN1269 protected cells exposed to Aß(1-42) , displayed central activity with respect to reducing Aß-induced neurotoxicity and was neuroprotective in electrophysiological and behavioural models of memory relevant to Aß-induced neurodegeneration. It represents a promising lead for designing inhibitors of Aß-mediated synaptic toxicity as potential neuroprotective agents for treating AD.
Original languageEnglish
Pages (from-to)383-392
Number of pages10
JournalBritish Journal of Pharmacology
Volume167
Issue number2
DOIs
Publication statusPublished - Sep 2012

ASJC Scopus subject areas

  • Pharmacology

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    Scopes, D. I. C., O'Hare, E., Jeggo, R., Whyment, A. D., Spanswick, D., Kim, E-M., Gannon, J., Amijee, H., & Treherne, J. M. (2012). Abeta oligomer toxicity inhibitor protects memory in models of synaptic toxicity. British Journal of Pharmacology, 167(2), 383-392. https://doi.org/10.1111/j.1476-5381.2012.01973.x