Reactions to a study published in Translational Psychiatry that shows suppressing beta-amyloid production in mice can reduce synapse loss and may provide direction for dementia treatments.
Dr James Pickett, Head of Research at Alzheimer’s Society said:
“It is sad that dementia is still the only leading cause of death that cannot be cured, prevented or slowed down. There haven’t be any new drugs last 15 years, so it’s very promising to have uncovered a reason why some of that research may have failed and a potential solution, which builds on our own previous research into this area.
‘Although only tested on mice in this instance, it is encouraging to see a drug already used in humans, fasudil, has the potential to reduce the build-up of amyloid. At this stage we don’t know if the effect will be the same in humans so further exploration is needed.
‘Repurposing existing drugs could be a real treasure trove, and the Alzheimer’s Society drug discovery programme is driving forwards opportunities for repurposing to find new treatments.”
Dr Carol Routledge, Director of Research at Alzheimer’s Research UK, said:
“The brain is a complex organ and its status quo depends on a careful orchestration of thousands of proteins. Detailed studies like this provide important insight into the knock-on effects that tweaking a single protein can have in the brain. As our knowledge of these complex interactions grows, so does our ability to refine and improve future drug discovery approaches.
“Dkk1 is a protein already being explored as a target for future dementia treatments, including by teams in the Alzheimer’s Research UK Drug Discovery Institutes. We know from current trials that drugs targeting amyloid need to be tested earlier in the disease, and Dkk1 could provide a promising new approach to overcome this challenge.
“While this study provides solid molecular evidence about an important molecular mechanism driving damage in Alzheimer’s, it is based on research in cells and mice. Fasudil is an approved drug for other health conditions, but is currently used in a critical care setting and would need to go through robust safety tests in trials of people with Alzheimer’s disease.”
Dr Diego Gomez-Nicola, Associate Professor in Neuroscience, University of Southampton, said:
“This is an interesting study shedding light into a mechanism to perpetuate the production of amyloid beta, one of the main pathological hallmarks of Alzheimer’s disease. The authors add support to existing data indicating that Dkk1 could be critical in the amyloid cascade, and this is important for our understanding of a slowly evolving chronic disease. I would be interested to see how this intervention can modify synaptic pathology in vivo, as this critical measure was not directly addressed in the current paper. I would be cautious in raising claims that this research demonstrates why anti-amyloid approaches have failed into clinical trials, as these are not supported by the present paper. Approaches aimed at clearing amyloid managed to achieved a reduction in amyloid load in many cases, but this was not associated with an improvement in cognition, hence the fail to meet primary outcomes. To put it in other words, cognitive decline was still able to progress in spite of a successful clearance of amyloid, which would contradict the authors claims about the amyloid production process being autonomously self-perpetuated. For these reasons, this hypothesis may benefit from further experimental work before moving into a clinical phase”
Prof Tara Spires-Jones, UK Dementia Research Institute Programme Lead, University of Edinburgh, said:
“This paper by Richard Killick and colleagues at King’s College London expands what we understand about how amyloid beta, one of the proteins that builds up in the brains of people with Alzheimer’s disease, affects the synaptic connections between brain cells. The scientists observe that in cells growing in a dish, amyloid beta starts a molecular cycle that increases its own production. They find that using a drug to inhibit this cycle is beneficial to cells. In one mouse model of Alzheimer’s disease, this same drug lowered amyloid levels. There were no experiments reported in this paper to show whether this helped the symptoms in the mice, although previous work from the same group did show a prevention of memory deficits in a different animal model with the same drug. This paper is scientifically interesting, but there is a long way to go to know whether these results will lead to therapies that will help people with dementia.”
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Prof Tara Spires-Jones: “I do not have any conflicts with this work.”
None others received.