A team of researchers from King’s College London and the Autonomous University of Madrid have revealed new insights into a molecular process in the brain that gets stuck in a vicious cycle during Alzheimer’s disease. The findings, based on research in mice, suggest that targeting this process could be a promising avenue in the search for effective new drug treatments for the disease.
One of the earliest events in Alzheimer’s disease is the build-up of an abnormal protein called amyloid in the brain. Amyloid is known to damage the way nerve cells in the brain communicate, breaking the connection points called ‘synapses’ that keep signals moving quickly across the brain. Amyloid is itself produced by a protein called Amyloid Precursor Protein (APP).
The team used cells in a dish and mice bred to show features of Alzheimer’s to investigate the mechanism by which APP and amyloid damage nerve cell communication.
They showed that APP can trigger a protein called DKK1, which can in turn, trigger a vicious cycle of events that damages synapses and drives more amyloid to be made. Over time, this damage worsens to the extent where current experimental drugs to target amyloid may no longer be effective.
The team identified a drug called fasudil, currently used to treat cerebral vasospasm, which can specifically block the negative action of DKK1 in the brain. In mice, they found that the drug was able to stop this harmful cycle of events and limit the build-up of amyloid in the brain. The researchers suggest that targeting DKK1 could be an effective treatment approach in light of recent negative clinical trials of drugs targeting amyloid directly.
The findings build on earlier work by the team supported by a PhD Studentship grant from Alzheimer’s Research UK.
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.”
“It’s been over 15 years since the last treatment for Alzheimer’s became available to patients. We must speed up the search for new treatments and today, Alzheimer’s Research UK is announcing a commitment to fund a further £250m of life-changing dementia research by 2025.”