Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil
<strong>Introduction</strong> 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 previous...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Elsevier
2017
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| _version_ | 1826284576478068736 |
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| author | Sellers, K Elliott, C Jackson, J Ghosh, A Ribe, E Rojo, A Jarosz-Griffiths, H Watson, I Xia, W Semenov, M Morin, P Hooper, N Porter, R Preston, J Al-Shawi, R Baillie, G Lovestone, S Cuadrado, A Harte, M Simons, P Srivastava, D Killick, R |
| author_facet | Sellers, K Elliott, C Jackson, J Ghosh, A Ribe, E Rojo, A Jarosz-Griffiths, H Watson, I Xia, W Semenov, M Morin, P Hooper, N Porter, R Preston, J Al-Shawi, R Baillie, G Lovestone, S Cuadrado, A Harte, M Simons, P Srivastava, D Killick, R |
| author_sort | Sellers, K |
| collection | OXFORD |
| description | <strong>Introduction</strong> 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. <strong>Methods</strong> 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. <strong>Results</strong> 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. <strong>Discussion</strong> 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. |
| first_indexed | 2024-03-07T01:15:55Z |
| format | Journal article |
| id | oxford-uuid:8ea7a1d9-0656-4ec8-a632-71606a6521f2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:15:55Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:8ea7a1d9-0656-4ec8-a632-71606a6521f22022-03-26T22:59:18ZAmyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudilJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8ea7a1d9-0656-4ec8-a632-71606a6521f2EnglishSymplectic Elements at OxfordElsevier2017Sellers, KElliott, CJackson, JGhosh, ARibe, ERojo, AJarosz-Griffiths, HWatson, IXia, WSemenov, MMorin, PHooper, NPorter, RPreston, JAl-Shawi, RBaillie, GLovestone, SCuadrado, AHarte, MSimons, PSrivastava, DKillick, R<strong>Introduction</strong> 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. <strong>Methods</strong> 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. <strong>Results</strong> 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. <strong>Discussion</strong> 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. |
| spellingShingle | Sellers, K Elliott, C Jackson, J Ghosh, A Ribe, E Rojo, A Jarosz-Griffiths, H Watson, I Xia, W Semenov, M Morin, P Hooper, N Porter, R Preston, J Al-Shawi, R Baillie, G Lovestone, S Cuadrado, A Harte, M Simons, P Srivastava, D Killick, R Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil |
| title | Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil |
| title_full | Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil |
| title_fullStr | Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil |
| title_full_unstemmed | Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil |
| title_short | Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil |
| title_sort | amyloid β synaptotoxicity is wnt pcp dependent and blocked by fasudil |
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