MAR 19, 2014 12:00 PM PDT

Abeta oligomer receptor antagonists as disease-modifying Alzheimers therapeutics

Presented at: Neuroscience
Speaker

Abstract

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic Amyloid beta (Abeta)1-42 oligomers is proposed to underlie cognitive decline in Alzheimers disease (AD). Synaptic binding of Abeta oligomers to several putative receptor proteins are reported to inhibit synaptic plasticity mechanisms such as long-term potentiation, affect membrane trafficking and induce reversible spine loss in hippocampal neurons, leading to impaired cognitive performance. We have discovered small molecules with high affinity for Abeta oligomer receptors that displace Abeta oligomer binding in vitro and in human AD patient brain tissue sections in a dose-dependent manner, and both prevent and reverse the effects of Abeta oligomers on membrane trafficking, synapse loss and cognitive deficits in AD mouse models. Our evidence suggests that despite structural heterogeneity, Abeta oligomers bind saturably and reversibly to specific receptors at synapses, and that the Abeta oligomer-induced synaptotoxicity underlying Alzheimers disease has a pharmacological basis that is amenable to treatment with small molecules. The compounds we have discovered therefore represent promising Alzheimers disease-modifying therapeutic drug candidates.


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MAR 19, 2014 12:00 PM PDT

Abeta oligomer receptor antagonists as disease-modifying Alzheimers therapeutics

Presented at: Neuroscience

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