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Amyloid ß synaptotoxicity is Wnt-PCP dependent and blocked by fasudil.
Sellers, Katherine J; Elliott, Christina; Jackson, Joshua; Ghosh, Anshua; Ribe, Elena; Rojo, Ana I; Jarosz-Griffiths, Heledd H; Watson, Iain A; Xia, Weiming; Semenov, Mikhail; Morin, Peter; Hooper, Nigel M; Porter, Rod; Preston, Jane; Al-Shawi, Raya; Baillie, George; Lovestone, Simon; Cuadrado, Antonio; Harte, Michael; Simons, Paul; Srivastava, Deepak P; Killick, Richard.
Afiliación
  • 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.
Alzheimers Dement ; 14(3): 306-317, 2018 03.
Article en En | MEDLINE | ID: mdl-29055813
ABSTRACT

INTRODUCTION:

Synapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid ß (Aß) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aß 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 Aß and of Dkk1 on synapse morphology and memory impairment while inhibiting or silencing key elements of the Wnt-PCP pathway.

RESULTS:

We demonstrate that Aß 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sinapsis / Péptidos beta-Amiloides / Nootrópicos / Fármacos Neuroprotectores / 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina / Vía de Señalización Wnt Límite: Animals Idioma: En Revista: Alzheimers Dement Año: 2018 Tipo del documento: Article País de afiliación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sinapsis / Péptidos beta-Amiloides / Nootrópicos / Fármacos Neuroprotectores / 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina / Vía de Señalización Wnt Límite: Animals Idioma: En Revista: Alzheimers Dement Año: 2018 Tipo del documento: Article País de afiliación: Reino Unido