The findings, published in ACS Chemical Neuroscience, suggest the compound Cu(ATSM) may help restore an important function of the blood-brain barrier. By repairing a key waste-removal system, the treatment could open the door to new therapies aimed at neurovascular dysfunction, a major factor in 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 builds up in the brain. Under normal conditions, these proteins are transported out of the brain and into the bloodstream through the blood-brain barrier.

A major part of that process relies on specialized transport proteins known as P-glycoprotein (P-gp) pumps. In people with Alzheimer’s, these pumps become much less effective, reducing the brain’s ability to remove harmful waste and allowing amyloid-beta to accumulate.

Lead author Dr. Jae Pyun of the Drug Delivery, Disposition and Dynamics theme at the Monash Institute of Pharmaceutical Sciences (MIPS) said the treatment works by improving the function of the brain’s blood vessels, leading to lower levels of toxic proteins and measurable cognitive benefits.

“This is the first study to show that Cu(ATSM) can increase the abundance of P-gp clearance pumps in an Alzheimer’s model, by 24.1 percent, effectively linking the repair of the blood-brain barrier to a reduction in toxic proteins and improved cognitive function,” Dr. Pyun said.

“By improving the pumps, the brain can finally clear out the trapped waste. Over 56 days, the treatment reduced toxic amyloid-beta by 42 percent and improved spatial learning by nearly 44 percent.”

Existing Drug Candidate Shows Promise

Senior author Professor Joseph Nicolazzo, Director of the Centre for Drug Candidate Optimisation at MIPS, said the drug may be able to move into human studies relatively quickly because it has already undergone safety testing for other neurological conditions.

“Cu(ATSM) is a copper compound with anti-inflammatory and neuroprotective properties that has already progressed to clinical testing for conditions like Parkinson’s and ALS,” Professor Nicolazzo said.

“Because reducing amyloid burden is clinically proven to improve functional outcomes, these preclinical results strongly support the rationale for testing this drug in early symptomatic Alzheimer’s disease.”

How Does the Brain Clear the Proteins?

Although the treatment significantly reduced amyloid-beta levels, researchers are still working to determine exactly how the proteins leave the brain after the blood-brain barrier is repaired.

The team believes the drug’s benefits may extend beyond restoring P-gp pumps. They suspect Cu(ATSM) could also enhance the activity of microglia, the brain’s immune cells, helping them consume and break down toxic amyloid plaques.

Future research will focus on identifying the precise pathways that allow these proteins to move from the brain into the bloodstream. According to the researchers, the results provide strong support for further investigation of biometal-based therapies such as Cu(ATSM) as potential treatments for blood vessel dysfunction and memory loss associated with Alzheimer’s disease.

Growing Need for New Alzheimer’s Treatments

Alzheimer’s disease and other forms of dementia continue to pose a major global health challenge. In Australia, dementia recently surpassed coronary heart disease to become the nation’s leading cause of death.

With populations aging and dementia-related deaths continuing to rise, researchers say the search for effective treatments that can slow or prevent cognitive decline remains an urgent priority.

The study was led by Dr. Jae Pyun and included co-authors Pranav Runwal, Oliver Fuller, Casey Egan, Professor Mark Febbraio, Associate Professor Jennifer Short and Professor Joseph Nicolazzo from the Monash Institute of Pharmaceutical Sciences, along with Dr. Asif Noor, Celeste Mawal, Professor Paul Donnelly, and Professor Ashley Bush from the University of Melbourne.