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

Sellers, K. J. et al. (2018) Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil. Alzheimer's and Dementia, 14(3), pp. 306-317. (doi: 10.1016/j.jalz.2017.09.008) (PMID:29055813) (PMCID:PMC5869054)

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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.

Item Type:Articles
Additional Information:This work was supported by MRC grants MR/M013944/1, awarded to R.K., MR/L021064/1, awarded to D.P.S., and by ARUK studentship grant no. ARUK-PhD2016-4, awarded to D.P.S. and R.K.
Glasgow Author(s) Enlighten ID:Elliott, Dr Christina and Baillie, Professor George
Authors: Sellers, K. J., Elliott, C., Jackson, J., Ghosh, A., Ribe, E., Rojo, A. I., Jarosz-Griffiths, H. H., Watson, I. A., Xia, W., Semenov, M., Morin, P., Hooper, N. M., Porter, R., Preston, J., Al-Shawi, R., Baillie, G., Lovestone, S., Cuadrado, A., Harte, M., Simons, P., Srivastava, D. P., and Killick, R.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Alzheimer's and Dementia
ISSN (Online):1552-5279
Published Online:19 October 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Alzheimer's and Dementia 14(3): 306-317
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
691651Pathway-driven identification of therapeutic targets for combating Alzheimer's disease.George BaillieMedical Research Council (MRC)MR/M013944/1RI CARDIOVASCULAR & MEDICAL SCIENCES