Summary: Researchers report a drug called fasudil may help to prevent synapse loss initiated by amyloid beta peptides in early stages of Alzheimer’s disease.
Source: King’s College London.
A recent multi-centre study, led by King’s College London and the University of Manchester, has established that synapse loss in Alzheimer’s disease is driven by a specific signalling pathway. This pathway is called the Wnt-planar cell polarity (PCP) signalling pathway and it may be pivotal to the progressive neurodegeneration seen in the disease.
The study, published in Alzheimer’s & Dementia, The Journal of the Alzheimer’s Association, also found that this process can be inhibited by the drug fasudil. Synapse loss is a key early event in Alzheimer’s disease, initiated by amyloid beta peptides – a hallmark protein in Alzheimer’s disease pathogenesis.
There are two Wnt signalling pathways; the canonical pathway (Wnt–catenin), which promotes synapse and neuronal maintenance; and the non-canonical pathway (Wnt-PCP), which promotes synaptic disassembly and degradation. These pathways will provide a balanced maintenance of synapses in a healthy individual, but in an Alzheimer’s disease brain the Wnt-PCP pathway is overactive and leads to synaptic loss.
Wnt-PCP synaptic signalling is triggered from the increased presence of amyloid beta protein, a characteristic hallmark of Alzheimer’s disease.
The group established that the Wnt-PCP pathway is critical to synapse loss, with the associated Alzheimer’s disease upregulation of amyloid beta driving this loss. To halt this synaptic damage and disease progression, the researchers investigated whether they could disrupt this pathway to stop the disease.
This was achieved by treatment in mice with a drug called fasudil. The drug targets a protein called ROCK in the Wnt-PCP signalling pathway, effectively derailing the synaptotoxic cascade of amyloid production.
The shutting off of the Wnt-PCP pathway with fasudil protected synaptic spines for degradation in the amyloid beta treated neurons in vitro. This result was further tested in an in vivo model of Alzheimer’s disease, where amyloid beta oligomer induced cognitive impairment was protected against by fasudil treatment.
Fasudil is a useful drug as it has previously been given clinical approval so is shown to be safe for humans. It was approved in 1994 for the treatment of cerebrovascular vasospasm, a condition where arterial spasms can lead to a reduced blood flow to the brain and neurodegeneration.
Dr Richard Killick from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, said: ‘There is currently no effective treatment for Alzheimer’s disease and there are millions of sufferers globally. As we all live longer, that number is only going to get bigger.
‘Our new study sheds a great deal of light on how beta-amyloid destroys the connections between nerve cells, in addition to identifying a drug which could potentially block this process.’
The success of fasudil within this study, coupled with its previous use in humans, warrant the further investigation of this drug for Alzheimer’s disease treatment.
About this neuroscience research article
Source: Jack Stonebridge – King’s College London Publisher: Organized by NeuroscienceNews.com. Image Source: NeuroscienceNews.com image is credited to Adrian Cousins/Wellcome Images. Original Research: Full open access research for “Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil” by 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, and Richard Killick in Alzheimer’s & Dementia. Published online October 19 2017 doi:10.1016/j.jalz.2017.09.008
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[cbtabs][cbtab title=”MLA”]King’s College London “Drug Could Derail Synapse Loss in Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 14 November 2017. <https://neurosciencenews.com/synapse-loss-alzheimers-drug-7952/>.[/cbtab][cbtab title=”APA”]King’s College London (2017, November 14). Drug Could Derail Synapse Loss in Alzheimer’s. NeuroscienceNews. Retrieved November 14, 2017 from https://neurosciencenews.com/synapse-loss-alzheimers-drug-7952/[/cbtab][cbtab title=”Chicago”]King’s College London “Drug Could Derail Synapse Loss in Alzheimer’s.” https://neurosciencenews.com/synapse-loss-alzheimers-drug-7952/ (accessed November 14, 2017).[/cbtab][/cbtabs]
Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil
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
“Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil” by 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, and Richard Killick in Alzheimer’s & Demential. Published online October 19 2017 doi:10.1016/j.jalz.2017.09.008