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.
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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 > 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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