Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil

Katherine J. Sellers, Christina Elliott, Joshua Jackson, Anshua Ghosh, Elena Ribe, Ana I. Rojo, 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 SimonsDeepak P. Srivastava, Richard Killick

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)306-317
Number of pages12
JournalAlzheimer's and Dementia
Volume14
Issue number3
DOIs
StatePublished - Mar 2018

Keywords

  • Alzheimer's disease
  • Amyloid
  • DAAM1
  • Dickkopf-1
  • Fasudil
  • Planar cell polarity
  • ROCK
  • Synapse
  • Synaptotoxicity
  • Wnt

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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