Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil.
Sellers KJ., Elliott C., Jackson J., Ghosh A., Ribe E., Rojo AI., Jarosz-Griffiths HH., Watson IA., Xia W., Semenov M., Morin P., Hooper NM., Porter R., Preston J., Al-Shawi R., Baillie G., Lovestone S., Cuadrado A., Harte M., Simons P., Srivastava DP., Killick R.
INTRODUCTION: Synapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid β (Aβ) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aβ 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 Aβ and of Dkk1 on synapse morphology and memory impairment while inhibiting or silencing key elements of the Wnt-PCP pathway. RESULTS: We demonstrate that Aβ 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.