WASP-1, a canonical Wnt signaling potentiator, rescues hippocampal synaptic impairments induced by Aβ oligomers

Amyloid-beta (A beta) oligomers are a key factor in Alzheimer's disease (AD)-associated synaptic dysfunction. A beta oligomers block the induction of hippocampal long-term potentiation (LTP) in rodents. The activation of Wnt signaling prevents A beta oligomer-induced neurotoxic effects. The compound WASP-1 (Wnt-activating small molecule potentiator-1), has been described as a synergist of the ligand Wnt-3a, enhancing the activation of Wnt/beta-catenin signaling. Herein, we report that WASP-1 administration successfully rescued AD-induced synaptic impairments both in vitro and in vivo. The activation of canonical Wnt/beta-catenin signaling by WASP-1 increased synaptic transmission and rescued hippocampal LTP impairments induced by A beta oligomers. Additionally, intra-hippocampal administration of WASP-1 to the double transgenic APPswe/PS1dE9 mouse model of AD prevented synaptic protein loss and reduced tau phosphorylation levels. Moreover, we found that WASP-1 blocked A beta aggregation in vitro and reduced pathological tau phosphorylation in vivo. These results indicate that targeting canonical Wnt signaling with WASP-1 could have value for treating AD. (C) 2014 Elsevier Inc. All rights reserved.