Amyloid Beta Synaptotoxicity Is Wnt-Pcp Dependent And Blocked By Fasudil

Introduction: Synapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid beta (A beta) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that A beta induces Dickkopf-1 (Dkk1), which in turn activates the Wnt-planar cell polarity (Wnt-PCP) pathway to drive tau pathology and neuronal death.Methods: We compared the effects of A beta and of Dkk1 on synapse morphology and memory impairment while inhibiting or silencing key elements of the Wnt-PCP pathway.Results: We demonstrate that A beta synaptotoxicity is also Dkk1 and Wnt-PCP dependent, mediated by the arm of Wnt-PCP regulating actin cytoskeletal dynamics via Daam1, RhoA and ROCK, and can be blocked by the drug fasudil.Discussion: Our data add to the importance of aberrant Wnt signaling in Alzheimer's disease neuropathology and indicate that fasudil could be repurposed as a treatment for the disease. (C) 2017 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.