Researchers at Monash University have identified a promising new approach to tackling Alzheimer’s disease. Laboratory studies have found that copper-based drugs not only reduce the accumulation of toxic proteins associated with the disease, but also improve long-term spatial memory.
The survey results are ACS Chemical Neurosciencesuggesting that the compound Cu(ATSM) may help restore important functions of the blood-brain barrier. By restoring a key waste removal system, this treatment could open the door to new treatments targeting neurovascular dysfunction, a key driver of Alzheimer’s disease.
Repairing the brain’s waste removal system
Alzheimer’s disease is associated with the accumulation of amyloid beta, a toxic protein that gradually accumulates in the brain. Under normal conditions, these proteins are transported from the brain through the blood-brain barrier into the bloodstream.
Much of that process relies on specialized transport proteins known as P-glycoprotein (P-gp) pumps. In people with Alzheimer’s disease, these pumps become significantly less effective, reducing the brain’s ability to remove harmful waste products and allowing amyloid beta to accumulate.
Dr Jae Pyung, lead author of the Drug Delivery, Properties and Kinetics theme at the Monash Institute for Pharmaceutical Sciences (MIPS), said the treatment works by improving the function of blood vessels in the brain, leading to lower levels of toxic proteins and measurable cognitive benefits.
“This is the first study to show that Cu(ATSM) increases the abundance of P-gp clearance pumps by 24.1 percent in an Alzheimer’s disease model, effectively linking blood-brain barrier repair to the reduction of toxic proteins and improved cognitive function,” said Dr. Pyun.
“By improving the pump, the brain can eventually get rid of trapped waste products. Treatment over 56 days reduced toxic amyloid beta by 42 percent and improved spatial learning by nearly 44 percent.”
Show that existing drug candidates are promising
Professor Joseph Nicolazzo, director of the Center for Drug Candidate Optimization at MIPS and lead author, said the drug had already undergone safety testing in other neurological conditions, so it could be moved to human studies relatively quickly.
“Cu(ATSM) is a copper compound with anti-inflammatory and neuroprotective properties that is already in clinical trials for conditions such as Parkinson’s disease and ALS,” Professor Nicolazzo said.
“These preclinical results strongly support the rationale for testing this drug in early symptomatic Alzheimer’s disease, as it is clinically proven that reducing amyloid burden improves functional outcomes.”
How does the brain remove proteins?
Although this treatment has significantly reduced amyloid beta levels, researchers are still working to understand exactly how the protein exits the brain after the blood-brain barrier is repaired.
The research team believes that the drug’s effects may go beyond restoring the P-gp pump. They suspect that Cu(ATSM) may increase the activity of microglia, the brain’s immune cells, to help consume and break down toxic amyloid plaques.
Future research will focus on identifying the exact pathways that allow these proteins to travel from the brain to the bloodstream. According to the researchers, the results strongly support further investigation of biometal-based therapies such as Cu(ATSM) as potential treatments for vascular dysfunction and memory loss associated with Alzheimer’s disease.
Growing need for new Alzheimer’s disease treatments
Alzheimer’s disease and other dementias continue to be a major global health challenge. In Australia, dementia recently surpassed coronary heart disease as the country’s leading cause of death.
As the population ages and dementia-related deaths continue to rise, the search for effective treatments that can slow or prevent cognitive decline remains an urgent priority, researchers say.
The study was led by Dr Jae Pyun, with co-authors including Professor Pranav Runwal, Professor Oliver Fuller, Professor Casey Egan, Professor Mark Febbraio, Associate Professor Jennifer Short and Professor Joseph Nicolazzo from the Monash Institute of Pharmaceutical Sciences, as well as Dr Asif Noor, Professor Celeste Mawal, Professor Paul Donnelly and Professor Ashley Bush from the University of Melbourne.
