Monash University researchers have found in laboratory experiments that a drug which delivers copper to the brain significantly reduces toxic Alzheimer’s proteins and improves long-term spatial memory.
The study, published today in the journal ACS Chemical Neuroscience, shows the compound Cu(ATSM) repairs a vital waste-clearing pump at the blood-brain barrier – unlocking a potential new avenue of therapeutics targeting neurovascular dysfunction, caused by one of the world’s leading causes of death.
Alzheimer’s is driven by the buildup of toxic proteins called amyloid-beta. Normally, the brain flushes these out into the bloodstream through the blood-brain barrier. In Alzheimer’s, the pumps doing the heavy lifting, called P-glycoprotein (P-gp), weaken significantly, clogging the drain and trapping the toxic proteins in the brain.
Lead author Dr Jae Pyun, from the Drug Delivery, Disposition and Dynamics theme at Monash Institute of Pharmaceutical Sciences (MIPS), whose work on the study marked the final part of his PhD project, said the treatment successfully engages the brain’s blood vessels to lower toxic protein levels, which results in behavioural 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 per cent, 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 per cent and improved spatial learning by nearly 44 per cent.”
Senior author Professor Joseph Nicolazzo, the Director of the Centre for Drug Candidate Optimisation at MIPS, said the compound has strong potential to quickly transition into human clinics because it has already undergone safety evaluations for other diseases.
“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.”
While the compound reduced amyloid buildup, researchers are still mapping the exact biological routes the proteins take to leave the brain. Beyond repairing the blood-brain barrier, the researchers suspect the copper treatment may empower the brain’s own immune cells, called microglia, to consume and degrade the toxic plaques.
Future studies will focus on tracking the precise clearance mechanisms to find how the proteins exit the brain into the bloodstream. The current findings establish a strong foundation for exploring biometal therapies like Cu(ATSM) to combat blood vessel dysfunction and memory loss in Alzheimer’s disease.
Alzheimer’s and other forms of dementia are a growing global health problem that recently became Australia’s leading cause of death, overtaking coronary heart disease. As mortality rates continue to climb and the population ages, finding effective treatments to halt cognitive decline is crucial.
Read the research paper: doi.org/10.1021
RESEARCHERS
This research was led by Dr Jae Pyun with 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.
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