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Amyloid beta synaptotoxicity is Wnt–planar cell polarity dependent and blocked by fasudil

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Katherine J. Sellers, Christina Elliott, Joshua Jackson, Anshua Ghosh, Elena Ribe, Ana Rojo-Sanchís, Heledd H. Jarosz-Griffiths, Iain A. Watson, Weiming Xia, Mikhail Semenov, Peter Morin, Nigel M. Hooper, Rod Porter, Jane Preston, Raya Al-Shawi, George Baillie, Simon Lovestone, Antonio Cuadrado, Michael Harte, Paul Simons & 2 more Deepak P. Srivastava, Richard Killick

Original languageEnglish
JournalAlzheimer's & Dementia
Early online date19 Oct 2017
Publication statusE-pub ahead of print - 19 Oct 2017


King's Authors


Introduction Synapse loss is the basis of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease (AD) sufferer's amyloid beta (Aβ) peptides aggregate to form senile plaques but as soluble peptides that 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 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 place Wnt-PCP signaling at the center of AD neuropathology and indicate that fasudil could be repositioned as a treatment for AD.

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