Cu(ATSM) Shows Promise for Alzheimer’s Treatment in Mice

Clearing harmful waste is among the brain’s most vital functions, and damage and disease can rapidly follow when its clearance systems begin to fail.

Repairing these systems may offer an effective route to treating Alzheimer’s, and scientists at Monash University and the University of Melbourne in Australia have identified a potential compound for the job.

The team investigated Cu(ATSM), a copper-containing compound that has already entered clinical testing for other neurodegenerative conditions. In Alzheimer’s mouse models, Cu(ATSM) reduced the accumulation of amyloid-beta protein clumps, which frequently build up in the brains of people with Alzheimer’s.

The mice also showed a marked improvement in long-term spatial memory, which helps them navigate their surroundings. How Cu(ATSM) achieves these effects is particularly worth investigating, as the approach may also have value in other neurodegenerative conditions.

Cu(ATSM) and the brain’s copper balance

Copper is needed for a healthy brain, while an imbalance in this metal has been associated with Alzheimer’s.

"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," says pharmaceutical scientist Joseph Nicolazzo, from Monash University.

A protein known as P-glycoprotein (P-gp) plays a part in the brain’s waste-removal process. This transporter helps move amyloid-beta out of the brain through the blood-brain barrier, but both its abundance and activity may decrease in Alzheimer’s disease.

For this study, Cu(ATSM) was delivered to target the P-gp pumps responsible for waste clearance. The researchers aimed to restore normal P-gp levels with the copper compound, allowing the pumps to remove more amyloid beta from the brain.

Alzheimer’s mouse-model results

The strategy was successful. P-gp levels rose in the brains of treated mice, while levels of the most toxic form of amyloid beta fell 42 percent. Spatial-memory performance also increased by almost 44 percent during the study’s 56 days.

"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," says pharmaceutical scientist Jae Pyun, from Monash University.

"Effectively linking the repair of the blood-brain barrier to a reduction in toxic proteins and improved cognitive function."

Although the findings are encouraging, considerable further work is needed before Cu(ATSM) can be confirmed as an effective Alzheimer’s treatment. Most importantly, the method must be tested in people with the disease rather than solely in animal models.

Notably, despite favourable animal findings, a pilot comparative analysis concluded that Cu(ATSM) produced no significant benefit in people with ALS.

Safety questions and future research

The researchers also want to examine more closely the processes that remove amyloid beta from the bloodstream and keep it away from the brain.

A clear understanding of these processes will be crucial to developing safe treatments. Copper levels increased throughout the bodies of the treated mice, although they did not reach levels considered dangerous.

"These increases in copper bioavailability are unexpected to have led to any toxicity in our studies, consistent with our observations," write the researchers in their published paper.

"Future work in Alzheimer's disease models should incorporate standard organ toxicity readouts and copper-dependent enzyme and oxidative stress panels to contextualize benefit-risk."

The evidence shows that Alzheimer’s is a complex disease, probably involving multiple interconnected causes and consequences. This complexity partly explains why some previous treatments aimed at amyloid beta have been less successful than anticipated.

Nevertheless, researchers are gradually assembling the pieces of the puzzle. These findings are encouraging for Cu(ATSM)’s potential to help the tens of millions of people worldwide living with Alzheimer’s.

"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," says Nicolazzo.

The research was published in ACS Chemical Neuroscience.