Axitinib, a chemotherapy drug that inhibits the growth of blood vessels, can improve cognition, memory, and behaviour in mice showing signs of Alzheimer’s disease.
A new study by researchers from the University of British Columbia has discovered that a drug that is commonly used to treat kidney cancer can restore memory and cognitive function in mice that exhibit symptoms of Alzheimer’s disease, bringing hopes of a more effective therapeutic strategy to combat Alzheimer’s and related vascular brain diseases.
Estimated to plague around 50 million people worldwide, Alzheimer’s disease is a progressive neurological dementia that gradually destroys one’s memory and thinking skills. The memory loss and confusion caused can become so debilitating that daily tasks such as driving, shopping, and paying bills become increasingly difficult.
In recent years, scientists have developed a variety of treatments based on the pathogenesis of Alzheimer’s disease, with a special interest in the tau protein or the amyloid-beta protein fragment as pharmacological targets. However, many such therapeutics have proven to be unsuccessful as they are considered “symptomatic” agents that merely improve cognitive and behavioural symptoms but do not address the underlying course of the disease.
“Other than some controversial recent results, there’s been a paucity of success in these clinical trials. So, a great deal of effort appears to have been directed toward the wrong targets for reversing Alzheimer’s disease,” said Professor Wilf Jefferies, the study’s senior author and principal investigator at the Centre for Blood Research, Vancouver Prostate Centre and Michael Smith Laboratories.
In a bid to reinvent the therapeutic pipeline for Alzheimer’s, Dr. Chaahat Singh and his colleagues at the university turned away from these traditional targets and chose to explore other potential disease targets, one of which is the blood-brain barrier. According to some research, the breakdown of the blood-brain barrier can allow proteins and fragments like the tau and beta-amyloid to enter, thereby seeding toxic plaques associated with cognitive decline.
In a previous study by Professor Jeffries, he found that the proliferation of blood vessels can compromise the blood-brain barrier in patients with Alzheimer’s disease. The highly selective blood-brain barrier serves to protect the brain from infections caused by invading foreign molecules. Because cancerous tumours also rely on the formation of new blood vessels to survive and thrive, the researchers believed that halting angiogenesis in Alzheimer’s may curb its debilitating effects. Therefore, they chose to investigate whether the anti-cancer drug, Axitinib, which inhibits the growth of new blood vessels, can prevent Alzheimer’s.
“Axitinib, the anti-cancer drug we used, blocks a receptor in the brain called a tyrosine kinase receptor, which is partly responsible for spurring blood vessel formation,” explained Dr. Singh, the paper’s first author. “It stops abnormal blood vessels from growing, which then prevents many downstream effects.”
Using mice models of Alzheimer’s disease, the scientists administered Axitinib for a month and studied how the treatment affected the mice on a molecular level. Results from their experiment showed that the mice experienced a dramatic reduction in blood vessel growth, leakage of the blood-brain barrier, and formation of the amyloid plaques. But most importantly, the mice demonstrated profound improvements in cognitive performance.
To assess the cognition and memory of the mice, the team performed a series of tests including maze test, fear, and conditioning tests. The maze test involved training the mice to reach a reward through a maze – a typical test to measure learning and memory. While a healthy mouse can find its way back to the reward, an animal demonstrating symptoms of Alzheimer’s disease cannot. However, mice with Alzheimer’s disease that underwent the therapy performed remarkably well in these tests, showing improvements in spatial awareness and memory.
“We are really very excited, because these findings suggest we can repurpose approved anti-cancer drugs for use as treatments for Alzheimer’s disease,” said Professor Jefferies. “It could shorten the clinical development by years.”
Although this research is still in its early stages and further study and clinical trials will be needed to assess the effectiveness of Axitinib in human patients with Alzheimer’s disease and its safety for long-term-use in elderlies, the team is optimistic as their results highlight the potential of tackling the disease through alternative pathways and reversing its effects completely.
“Researchers including myself have been disappointed in observing numerous clinical trials for Alzheimer’s disease fail to reach their clinical endpoints,” said Prof. Jefferies. “The therapeutic approach we discovered has an opportunity to revise the clinical treatment of Alzheimer’s patients, which I think is absolutely needed at this point for the field to advance.”
Source: Singh et al. (2021). Reversing pathology in a preclinical model of Alzheimer’s disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics. EBioMedicine, 71, 103503.