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

Autor:	Sellers KJ; King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK., Elliott C; King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK., Jackson J; The University of Manchester, Faculty of Biology, Medicine and Health, Division of Pharmacy and Optometry, Manchester, UK., Ghosh A; King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK., Ribe E; University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, UK., Rojo AI; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). Instituto de Investigación Sanitaria La Paz (IdiPaz), Autonomous University of Madrid, Madrid, Spain., Jarosz-Griffiths HH; The University of Manchester, Faculty of Biology, Medicine and Health, Division of Neuroscience and Experimental Psychology, Manchester, UK., Watson IA; King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK., Xia W; Boston University School of Medicine, New England Geriatric Research Education and Clinical Center, Boston, USA., Semenov M; Boston University School of Medicine, New England Geriatric Research Education and Clinical Center, Boston, USA., Morin P; Boston University School of Medicine, New England Geriatric Research Education and Clinical Center, Boston, USA., Hooper NM; The University of Manchester, Faculty of Biology, Medicine and Health, Division of Neuroscience and Experimental Psychology, Manchester, UK., Porter R; Rod Porter, Rod Porter Consultancy, Baldock, England, UK., Preston J; King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, London, UK., Al-Shawi R; University College London, Centre for Amyloidosis and Acute Phase Proteins, Royal Free Campus, London, UK., Baillie G; University of Glasgow, Institute of Cardiovascular and Medical Science, Glasgow, Scotland., Lovestone S; University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, UK., Cuadrado A; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). Instituto de Investigación Sanitaria La Paz (IdiPaz), Autonomous University of Madrid, Madrid, Spain., Harte M; The University of Manchester, Faculty of Biology, Medicine and Health, Division of Pharmacy and Optometry, Manchester, UK., Simons P; University College London, Centre for Amyloidosis and Acute Phase Proteins, Royal Free Campus, London, UK., Srivastava DP; King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK. Electronic address: Deepak.Srivastava@kcl.ac.uk., Killick R; King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK. Electronic address: Richard.1.Killick@kcl.ac.uk.
Jazyk:	angličtina
Zdroj:	Alzheimer's & dementia : the journal of the Alzheimer's Association [Alzheimers Dement] 2018 Mar; Vol. 14 (3), pp. 306-317. Date of Electronic Publication: 2017 Oct 19.
DOI:	10.1016/j.jalz.2017.09.008
Abstrakt:	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. (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz: