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Alzheimers Dement. 2018 Mar;14(3):306-317. doi: 10.1016/j.jalz.2017.09.008. Epub 2017 Oct 19.

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

Author information

1
King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
2
The University of Manchester, Faculty of Biology, Medicine and Health, Division of Pharmacy and Optometry, Manchester, UK.
3
University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, UK.
4
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). Instituto de Investigación Sanitaria La Paz (IdiPaz), Autonomous University of Madrid, Madrid, Spain.
5
The University of Manchester, Faculty of Biology, Medicine and Health, Division of Neuroscience and Experimental Psychology, Manchester, UK.
6
Boston University School of Medicine, New England Geriatric Research Education and Clinical Center, Boston, USA.
7
Rod Porter, Rod Porter Consultancy, Baldock, England, UK.
8
King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, London, UK.
9
University College London, Centre for Amyloidosis and Acute Phase Proteins, Royal Free Campus, London, UK.
10
University of Glasgow, Institute of Cardiovascular and Medical Science, Glasgow, Scotland.
11
King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK. Electronic address: Deepak.Srivastava@kcl.ac.uk.
12
King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK. Electronic address: Richard.1.Killick@kcl.ac.uk.

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.

KEYWORDS:

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

PMID:
29055813
PMCID:
PMC5869054
DOI:
10.1016/j.jalz.2017.09.008
[Indexed for MEDLINE]
Free PMC Article

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