As researchers continue to search for the causes behind Alzheimer's disease and age-related dementia, one possibility is that a leaky blood-brain barrier could have a role to play, allowing for the easy passage of harmful proteins. A new study has explored how this defense might be shored up through the use of an existing anti-cancer drug, with the authors demonstrating some promising results around the reversal of cognitive decline in mice.
The blood-brain barrier is an almost impenetrable membrane that prevents harmful particles from entering, and is therefore key to maintaining the health of the organ and human body as a whole. One line of thinking when it comes to Alzheimer's disease is that a breakdown in this important barrier can allow proteins and fragments such as tau and beta-amyloid to enter, seeding toxic plaques associated with cognitive decline.
In recent years, studies have shown how these leaks could act as early warning signs for Alzheimer's, and how they allow blood-clotting proteins to enter the brain that cause damage to the synapses. One 2019 study even showed how an anti-inflammatory drug can counter the harmful effects of these invasive proteins and reverse cognitive decline associated with dementia in mice.
For this latest study, scientists at the University of British Columbia looked to build on some of their previous research demonstrating how these problematic leaks in the blood-brain barrier could be the result of proliferating blood vessels. This pointed them toward the idea that an agent that prevents irregular formation of blood vessels could put the brakes on this process, which in turn led them to an already-approved chemotherapy drug called Axitinib.
“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. Chaahat Singh, the paper’s first author. “It stops abnormal blood vessels from growing, which then prevents many downstream effects.”
Working with mouse models of Alzheimer's, the scientists administered Axitinib over the course of a month and then used molecular analysis to study the effects on the rodents. This revealed a dramatic reduction in blood vessel growth, leakage of the blood-brain barrier and formation of amyloid plaques. Assessments were then carried out to assess the cognition and memory of the mice, including maze tests and fear and conditioning tests, which showed profound reductions in cognitive impairment.
“We are really very excited, because these findings suggest we can repurpose approved anti-cancer drugs for use as treatments for Alzheimer’s disease,” says Professor Wilf Jefferies, the study’s senior author. “It could shorten the clinical development by years.”
It is important to note that this research is still in its very early stages. More study is required to ascertain the safety of subjecting older subjects to a long-term Alzheimer's treatment regime involving a chemotherapy drug. And that's if these results can be translated from mice to humans in the first place.
Despite these sizable "ifs" the results are promising in that they further highlight the potential of an alternative pathways to tackle Alzheimer's. Many clinical trials have involved drugs designed to take out harmful brain plaques as a way of treating Alzheimer's, and almost all have failed in clinical trials. Studies such as this one add weight to the idea that the disease could be treated in other ways.
“Researchers including myself have been disappointed in observing numerous clinical trials for Alzheimer’s disease fail to reach their clinical endpoints,” says 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.”
The research was published in the journal EBioMedicine.
Source: University of British Columbia
