A? oligomer toxicity inhibitor protects memory in models of synaptic toxicity.

ABSTRACT:

Background and purpose

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

Experimental approach

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

Conclusions and implications

SEN1269 protected cells exposed to A?(1-42) , displayed central activity with respect to reducing A?-induced neurotoxicity and was neuroprotective in electrophysiological and behavioural models of memory relevant to A?-induced neurodegeneration. It represents a promising lead for designing inhibitors of A?-mediated synaptic toxicity as potential neuroprotective agents for treating AD.

SUBMITTER: Scopes DI 

PROVIDER: S-EPMC3481045 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature