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

Sellers, KJ; Elliott, C; Jackson, J; Ghosh, A; Ribe, E; Rojo-Sanchís, A; Jarosz-Griffiths, HH; ... Killick, R; + view all (2017) Amyloid beta synaptotoxicity is Wnt-planar cell polarity dependent and blocked by fasudil. Alzheimer's & Dementia 10.1016/j.jalz.2017.09.008. Green open access

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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.

Type: Article
Title: Amyloid beta synaptotoxicity is Wnt-planar cell polarity dependent and blocked by fasudil
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jalz.2017.09.008
Publisher version: http://doi.org/10.1016/j.jalz.2017.09.008
Language: English
Additional information: Copyright © 2017 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Alzheimer's, Amyloid, DAAM1, Dickkopf-1, Fasudil, Planar cell polarity, ROCK, Synapse, Synaptotoxicity, Wnt
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10033185
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