Recent research published in journals ACS Chemical Neuroscience The findings suggest that drugs that deliver copper can repair important waste removal systems in the brain and reduce levels of toxic Alzheimer’s disease proteins. By restoring these cellular pumps, this treatment provides evidence of improved learning and spatial memory in animal models of this disease.
Alzheimer’s disease is a progressive brain disease characterized by memory loss and decline in cognitive function. The main feature of this disease is the accumulation of amyloid beta. This is a naturally occurring protein fragment that tends to clump together to form toxic plaques in the brain. In a healthy biological system, the body continues to flush these proteins from brain tissue into the bloodstream.
This waste removal process is highly dependent on the blood-brain barrier. This structure is a highly selective cell border that protects the brain from harmful substances in the blood. It also allows the passage of essential nutrients. Embedded within the blood-brain barrier is a specialized transport protein known as P-glycoprotein. These proteins act like cellular pumps, grabbing amyloid beta and pushing it out of the central nervous system.
People with Alzheimer’s disease tend to have significantly reduced amounts of P-glycoprotein. With fewer pumps available, the brain loses its ability to effectively remove amyloid beta, and the toxic protein accumulates. Previous research has shown that repairing these pumps or increasing their number may help clear harmful plaques from the brain.
Study author Ashley Bush, professor and clinical lead in the Mental Health Research Priority Area at the University of Melbourne, explained the specific motivation behind the study. “Alzheimer’s disease (AD) is a major burden, and the drugs available for treatment are only modestly effective, meaning there remains a large unmet pharmacological need,” said Bush. “One of the characteristic pathology of Alzheimer’s disease is the accumulation of beta-amyloid (Aβ) in the brain.”
In addition to plaque buildup, scientists have observed that other troubling cellular mechanisms are at work in this disease. “There are also signs of cell death through an iron-dependent suicidal process called ferroptosis,” Bush said. Ferroptosis occurs when iron accumulation causes overwhelming oxidative stress, destroying cells from the inside out.
Bush pointed to previous experiments linking copper supplies to potential solutions to both problems. “We previously discovered that CuATSM, a copper-containing drug with antiferroptotic properties, increases levels of P-glycoprotein (P-gp), a protein present on the vasculature that plays a role in the excretion of Aβ in the brain,” Bush said. “We therefore wanted to test the twinned antiferroptosis and pro-PGP benefits of CuATSM in a mouse model of AD.”
To investigate this, the researchers used a genetically modified mouse model known as the APP/PS1 mouse. These mice have been engineered to produce too much human amyloid beta and have become the standard test subject for studying familial Alzheimer’s disease. The authors focused on 8-month-old female mice. At this stage, amyloid plaques and memory impairment are well established in this strain.
The researchers divided the mice into different groups and administered either 30 milligrams of Cu (ATSM) per kilogram of body weight orally or a neutral placebo solution. Healthy non-transgenic mice were also included as baseline controls. Six to seven mice per group were used for biochemical tests, and groups of 16 to 20 mice were evaluated for behavioral tests. The total treatment regimen lasted 56 days.
Lead author Jae Pyun summarized the results, saying the research was the final part of a PhD project on drug delivery, properties and dynamics at the Monash Institute of Pharmaceutical Sciences. “This is the first study to show that Cu(ATSM) can increase 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,” Pyun said. “By improving the pump, the brain will eventually be able to remove trapped waste products.”
After the treatment period, the authors measured the amount of P-glycoprotein in small blood vessels in the brain. They isolated these microvessels and used specialized protein analysis techniques. Untreated Alzheimer’s disease mice showed a 30.6 percent reduction in P-glycoprotein compared to healthy control mice, but these structures were significantly restored in treated mice. Pyun mentioned a broader effect. “This treatment reduced toxic amyloid beta by 42 percent and improved spatial learning by nearly 44 percent over 56 days.”
The researchers also used mass spectrometry to measure metal levels in living tissues. They found that Cu(ATSM) successfully delivered its payload and increased copper concentrations in brain microvessels by nearly 230%. Similar increases in copper were observed in peripheral organs such as the liver, kidneys, and intestines.
To assess whether the repaired pumps were actively pumping out more waste, the scientists injected small amounts of radioactive amyloid beta directly into the mice’s brains. They tracked how much radioactive material remained in the brain after two and 10 minutes. Untreated Alzheimer’s disease mice retained significantly more amyloid beta than healthy mice, confirming a deficiency in waste removal. Cu(ATSM) treatment showed a tendency to improve the removal rate by 11.9% at 10 minutes.
Alongside the biological tests, the researchers conducted a series of behavioral assessments. They tracked how often the mice explored new areas and tested their short-term spatial memory using a Y-maze. They also tested recognition memory by observing how much time the mice spent interacting with new and familiar objects. Alzheimer’s disease mice exhibited recognition memory deficits, but Cu(ATSM) treatment did not restore performance on these specific short-term tasks.
Next, the authors tested spatial learning and long-term memory using the Barnes maze. The device is a very bright circular platform with numerous holes around the edges, with only one hole leading to a secure dark box. Over four days of training, untreated Alzheimer’s mice struggled to learn the location of the escape hole. Mice treated with Cu(ATSM) showed progressive improvement, with fewer errors as the days progressed.
In a final memory test, the researchers tracked the animals’ path and speed. Treated Alzheimer’s mice found the escape box significantly faster than the untreated group. There are also fewer mistakes when identifying the correct hole. “The new drug candidates worked quickly and showed great efficacy,” Bush said. He added that he was particularly surprised that it took only 56 days of treatment to achieve a significant effect.
Interpreting these findings requires close attention to the specific biological mechanisms at play. Although the study linked a copper-delivery drug to lower amyloid levels and improved memory, it did not conclusively prove that the P-glycoprotein pump was the sole reason for plaque disappearance. The drug may also be acting through a secondary pathway, since radiological testing showed only a slight trend toward improvement.
One possibility is that the treatment activates microglia, the brain’s main immune cells. Microglia also possess P-glycoprotein, and copper compounds may stimulate these immune cells to actively consume and break down amyloid beta plaques from within brain tissue. Future research could examine exactly how proteins leave the brain by tracking radioactive markers in the bloodstream over time.
The researchers emphasize that this study is early preclinical data. “This is a mouse study, and we have a long way to go before testing it in humans,” Bush cautioned. Expanding this study to different disease models and longer observation periods will help reveal the full potential of this drug.
Looking ahead, scientists see multiple potential uses for this compound. “CuATSM is a PET contrast agent that has been reported to have increased signal in Alzheimer’s disease and other neurodegenerative diseases,” Bush said, referring to positron emission tomography, a type of medical scan that tracks cellular activity. “This signal may reflect ferroptosis. Final trials of ferroptosis inhibitors may be monitored by CuATSM.”
Joseph Nicolazzo, Professor and Director of the Center for Drug Candidate Optimization at the Monash Institute of Pharmaceutical Sciences and Associate Dean for International Studies in the School of Pharmacy and Pharmaceutical Sciences at Monash University, highlighted the drug’s clinical momentum. “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,” Nicolazzo said. “These preclinical results strongly support the rationale for testing this drug in early symptomatic Alzheimer’s disease, as reducing amyloid burden is clinically proven to improve functional outcomes.”
The research team aims to build on these findings by mapping precisely how biological repair occurs. Bush hopes readers will recognize that “this class of drugs significantly improves Alzheimer’s disease pathology and improves cognitive performance in mouse models of Alzheimer’s disease, so it deserves to be tested in clinical trials.”
The study, “Cu(ATSM) restores P-glycoprotein abundance in the blood-brain barrier and improves cognitive function in the APP/PS1 mouse model of Alzheimer’s disease,” was authored by Jae Pyun, Asif Noor, Pranav Runwal, Celeste Mawal, Oliver K. Fuller, Casey L. Egan, Mark A. Febbraio, and Paul S. Donnelly. Jennifer L. Short, Ashley I. Bush, Joseph A. Nicolazzo.
