Copper-delivering drug repairs brain pumps to clear toxic Alzheimer’s proteins

A recent study published in the journal ACS Chemical Neuroscience suggests that a copper-delivering drug can repair a vital waste-removal system in the brain, leading to lower levels of toxic Alzheimer’s proteins. By restoring these cellular pumps, the treatment provides evidence of improved learning and spatial memory in an animal model of the disease.

Alzheimer’s disease is a progressive brain condition marked by memory loss and cognitive decline. A primary feature of this disease is the buildup 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 continuously flushes these proteins out of the brain tissue and into the bloodstream.

This waste removal process relies heavily on the blood-brain barrier. This structure is a highly selective border of cells that protects the brain from harmful substances in the blood. It also allows essential nutrients to pass through. Embedded within the blood-brain barrier are specialized transport proteins known as P-glycoprotein. These proteins act like cellular pumps, grabbing amyloid-beta and pushing it out of the central nervous system.

In people with Alzheimer’s disease, the abundance of P-glycoprotein tends to decrease significantly. With fewer pumps available, the brain loses its ability to effectively remove amyloid-beta, causing the toxic proteins to accumulate. Previous research indicates that repairing or increasing the number of these pumps could help empty the brain of harmful plaques.

Study author Ashley Bush, a professor and clinical lead of the Mental Health Research Priority Area at the University of Melbourne, explained the specific motivation behind the research. “Alzheimer’s disease (AD) is a major burden, and the drugs available for treatment have modest effects, meaning that there is still a great unmet pharmacological need,” Bush said. “One of the signature pathologies of AD is the accumulation of beta-amyloid (Aβ) in the brain.”

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In addition to the buildup of plaques, scientists have observed other troubling cellular mechanisms at play in the disease. “There are also signs of cell death by an iron-dependent suicide process called ferroptosis,” Bush said. Ferroptosis happens when iron accumulation triggers overwhelming oxidative stress, destroying cells from the inside out.

Bush pointed to earlier experiments linking copper delivery to potential solutions for both problems. “We had previously found that CuATSM, a copper-carrying drug with anti-ferroptosis properties, boosted the levels of P-glycoprotein (P-gp), a protein found on the vasculature that plays a role in the exit of Aβ in the brain,” Bush said. “Thus, we wanted to test the twin anti-ferroptosis and the pro-PGP benefits of CuATSM in a mouse model of AD.”

To explore this, the researchers utilized a genetically modified mouse model known as the APP/PS1 mouse. These mice are engineered to overproduce human amyloid-beta, making them a standard subject for studying familial Alzheimer’s disease. The authors focused on female mice at eight months of age. At this stage, amyloid plaques and memory deficits are well established in this strain.

The scientists divided the mice into different groups to receive either a daily oral dose of Cu(ATSM) at 30 milligrams per kilogram of body weight or a neutral placebo liquid. They also included healthy, non-genetically modified mice as a baseline control. The biochemical tests used between six and seven mice per group, and the behavioral tests evaluated groups of 16 to 20 mice. The total treatment regimen lasted for 56 days.

Lead author Jae Pyun, whose work on the study marked the final part of his doctoral project in the Drug Delivery, Disposition and Dynamics theme at the Monash Institute of Pharmaceutical Sciences, summarized the outcomes. “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,” Pyun said. “By improving the pumps, the brain can finally clear out the trapped waste.”

Following the treatment period, the authors measured the abundance of P-glycoprotein in the tiny blood vessels of the brain. They isolated these microvessels and used specialized protein analysis techniques. The untreated Alzheimer’s mice exhibited a 30.6 percent reduction in P-glycoprotein compared to the healthy control mice, but the treated mice saw significant restoration of these structures. Pyun noted the broader impact: “Over 56 days, the treatment reduced toxic amyloid-beta by 42 percent and improved spatial learning by nearly 44 percent.”

The researchers also used mass spectrometry to measure metal levels in the biological tissue. They found that Cu(ATSM) successfully delivered its payload, increasing copper concentrations in the brain microvessels by nearly 230 percent. Similar increases in copper were observed in peripheral organs like the liver, kidneys, and intestines.

To evaluate whether the restored pumps were actively flushing out more waste, the scientists injected a small amount of radioactive amyloid-beta directly into the brains of the mice. They tracked how much of the radioactive material remained in the brain after two and ten minutes. The untreated Alzheimer’s mice retained significantly more amyloid-beta than the healthy mice, confirming a waste-removal deficit. The Cu(ATSM) treatment resulted in an 11.9 percent trend toward improved removal at the ten-minute mark.

Alongside the biological tests, the researchers administered a series of behavioral assessments. They tested short-term spatial memory using a Y-shaped maze, tracking how often the mice explored new areas. They also tested recognition memory by observing how much time the mice spent interacting with novel versus familiar objects. The Alzheimer’s mice displayed deficits in recognition memory, but the Cu(ATSM) treatment did not restore performance on these specific short-term tasks.

The authors then used the Barnes maze to test spatial learning and long-term memory. This apparatus is a highly lit circular platform with numerous holes around the edge, where only one hole leads to a safe dark box. Over four days of training, the untreated Alzheimer’s mice struggled to learn the location of the escape hole. The mice treated with Cu(ATSM) showed progressive improvement, making fewer errors as the days went on.

During the final memory test, the researchers tracked the path and speed of the animals. The treated Alzheimer’s mice found the escape box significantly faster than the untreated group. They also made fewer errors in identifying the correct hole. “The drug candidate worked rapidly and showed large effects,” Bush noted. He added that he was particularly surprised “that only 56 days of treatment were needed for conspicuous benefits.”

Interpreting these findings requires close attention to the specific biological mechanisms at play. The study links the copper-delivering drug to lower amyloid levels and better memory, but it does not definitively prove that the P-glycoprotein pumps are the sole reason for the disappearing plaques. Because the radioactive test only showed a slight trend toward improvement, the drug might also be working through secondary routes.

One possibility is that the treatment empowers microglia, which are the primary immune cells of the brain. Microglia also possess P-glycoprotein, and the copper compound may be stimulating these immune cells to actively consume and degrade the amyloid-beta plaques from within the brain tissue. Future studies could explore exactly how the proteins exit the brain by tracking the radioactive markers into the bloodstream over longer periods.

Researchers stress that this study represents early, preclinical data. “This was a study in mice, and there is a long road ahead for testing in humans,” Bush cautioned. Expanding this research to include different disease models and longer observation periods will help uncover the drug’s full potential.

Looking ahead, the scientists see multiple potential applications for the compound. “CuATSM is a PET imaging agent, and has been reported to have an increased signal in AD and other neurodegenerative disorders,” Bush said, referring to positron emission tomography, a type of medical scan that tracks cellular activity. “This signal may reflect ferroptosis. The eventual trialing of ferroptosis inhibitors could be monitored by CuATSM.”

Joseph Nicolazzo, a professor and director of the Centre for Drug Candidate Optimisation at the Monash Institute of Pharmaceutical Sciences, as well as the associate dean international of the Faculty 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 has already progressed to clinical testing for conditions like Parkinson’s and ALS,” 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.”

The research team aims to build on these findings by mapping exactly how the biological repairs take place. Bush hopes readers recognize “[t]hat this class of drug markedly improves AD pathology, and improves cognitive performance in a mouse model for AD, and deserves to be tested in clinical trials.”

The study, “Cu(ATSM) Restores Blood−Brain Barrier Abundance of P‑Glycoprotein 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, Paul S. Donnelly, Jennifer L. Short, Ashley I. Bush, and Joseph A. Nicolazzo.