A recent multi-centre study 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 researchers also discovered that this process can be inhibited by the repurposed 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.
Wnt Signalling Pathways
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. This protein will misfold and deposit around neurons and synapses leading to progressive neurodegeneration and cognitive decline.
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.
Fasudil Synapse Protection
This was achieved by treatment 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.
Crossing The Blood-Brain Barrier
The usefulness of fasudil for Alzheimer’s disease could be considered relatively strange, as the drug and its major active metabolite (hydroxyfasudil) both have previously been shown to have a relatively low penetrance to the central nervous system. Despite this, the current study established that fasudil and its major metabolite cross the blood-brain barrier at a rate of 8.5%; higher than some other central nervous system drugs like diazepam (3.6%) and clozapine (1.1%).
The synaptic protection of fasudil within the central nervous system after peripheral administration, exhibits the capability to cross the blood-brain barrier in high enough concentrations to elicit the beneficial results seen in this study.
Future For Therapies
The success of fasudil within this study, coupled with the previous safety tests in humans, warrant the further investigation of this drug for Alzheimer’s disease treatment.
Targeting proteins within the Wnt-PCP signalling pathway may offer multiple therapeutic options for synapse and neuron degenerating diseases (Huntington’s disease for example), not limited to fasudil and Alzheimer’s disease.
Current drug treatments for Alzheimer’s disease fail to treat the underlying causes of disease, by only treating symptomatic issues. A drug which stops or slows down the progression of Alzheimer’s disease is necessary to avoid the predicted mass increase of disease prevalence; hopefully drugs like fasudil will be able to circumvent the debilitating onset of Alzheimer’s disease.
Sellers KJ, Elliott C, Jackson J, Ghosh A, Ribe E, Rojo-Sanchís A, Jarosz-Griffiths HH, Watson IA, Xia W, Semenov M, Morin P, Hooper NM, Porter R, Preston J, Al-Shawi R, Baillie G1, Lovestone S, Cuadrado A, Harte M, Simons P, Srivastava DP, Killick R Amyloid beta synaptotoxicity is Wnt-planar cell polarity dependent and blocked by fasudil Alzheimers & Dementia. 2017 Oct 19. Doi: 10.1016/j.jalz.2017.09.008. [Epub ahead of print]
Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester. Image: Adrian Cousins/Wellcome Images