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

Katherine J. Sellers; Christina Elliott; Joshua Jackson; Anshua Ghosh; Elena Ribe; Ana I. Rojo; Heledd H. Jarosz-Griffiths; Iain A. Watson; Weiming Xia; Mikhail Semenov; Peter Morin; Nigel M. Hooper; Rod Porter; Jane Preston; Raya Al-Shawi; George Baillie; Simon Lovestone; Antonio Cuadrado; Michael Harte; Paul Simons; Deepak P. Srivastava; Richard Killick

doi:10.1016/j.jalz.2017.09.008

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

Katherine J. Sellers, Christina Elliott, Joshua Jackson, Anshua Ghosh, Elena Ribe, Ana I. Rojo, Heledd H. Jarosz-Griffiths, Iain A. Watson, Weiming Xia, Mikhail Semenov, Peter Morin, Nigel M. Hooper, Rod Porter, Jane Preston, Raya Al-Shawi, George Baillie, Simon Lovestone, Antonio Cuadrado, Michael Harte, Paul SimonsDeepak P. Srivastava, Richard Killick

Houston Methodist

Research output: Contribution to journal › Article › peer-review

86 Scopus citations

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.

Original language	English (US)
Pages (from-to)	306-317
Number of pages	12
Journal	Alzheimer's and Dementia
Volume	14
Issue number	3
DOIs	https://doi.org/10.1016/j.jalz.2017.09.008
State	Published - Mar 2018

Keywords

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

ASJC Scopus subject areas

Epidemiology
Health Policy
Developmental Neuroscience
Clinical Neurology
Geriatrics and Gerontology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1016/j.jalz.2017.09.008

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Sellers, K. J., Elliott, C., Jackson, J., Ghosh, A., Ribe, E., Rojo, A. I., Jarosz-Griffiths, H. H., Watson, I. A., Xia, W., Semenov, M., Morin, P., Hooper, N. M., Porter, R., Preston, J., Al-Shawi, R., Baillie, G., Lovestone, S., Cuadrado, A., Harte, M., ... Killick, R. (2018). Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil. Alzheimer's and Dementia, 14(3), 306-317. https://doi.org/10.1016/j.jalz.2017.09.008

Sellers, KJ, Elliott, C, Jackson, J, Ghosh, A, Ribe, E, Rojo, AI, Jarosz-Griffiths, HH, Watson, IA, Xia, W, Semenov, M, Morin, P, Hooper, NM, Porter, R, Preston, J, Al-Shawi, R, Baillie, G, Lovestone, S, Cuadrado, A, Harte, M, Simons, P, Srivastava, DP & Killick, R 2018, 'Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil', Alzheimer's and Dementia, vol. 14, no. 3, pp. 306-317. https://doi.org/10.1016/j.jalz.2017.09.008

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title = "Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil",

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",

author = "Sellers, \{Katherine J.\} and Christina Elliott and Joshua Jackson and Anshua Ghosh and Elena Ribe and Rojo, \{Ana I.\} and Jarosz-Griffiths, \{Heledd H.\} and Watson, \{Iain A.\} and Weiming Xia and Mikhail Semenov and Peter Morin and Hooper, \{Nigel M.\} and Rod Porter and Jane Preston and Raya Al-Shawi and George Baillie and Simon Lovestone and Antonio Cuadrado and Michael Harte and Paul Simons and Srivastava, \{Deepak P.\} and Richard Killick",

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year = "2018",

month = mar,

doi = "10.1016/j.jalz.2017.09.008",

language = "English (US)",

volume = "14",

pages = "306--317",

journal = "Alzheimer's and Dementia",

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T1 - Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil

AU - Sellers, Katherine J.

AU - Elliott, Christina

AU - Jackson, Joshua

AU - Ghosh, Anshua

AU - Ribe, Elena

AU - Rojo, Ana I.

AU - Jarosz-Griffiths, Heledd H.

AU - Watson, Iain A.

AU - Xia, Weiming

AU - Semenov, Mikhail

AU - Morin, Peter

AU - Hooper, Nigel M.

AU - Porter, Rod

AU - Preston, Jane

AU - Al-Shawi, Raya

AU - Baillie, George

AU - Lovestone, Simon

AU - Cuadrado, Antonio

AU - Harte, Michael

AU - Simons, Paul

AU - Srivastava, Deepak P.

AU - Killick, Richard

PY - 2018/3

Y1 - 2018/3

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Amyloid

KW - DAAM1

KW - Dickkopf-1

KW - Fasudil

KW - Planar cell polarity

KW - ROCK

KW - Synapse

KW - Synaptotoxicity

KW - Wnt

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AN - SCOPUS:85032892711

SN - 1552-5260

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EP - 317

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 3

ER -

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

Abstract

Keywords

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