Most copper in the brain presents an issue. It accumulates in inappropriate locations, fuels the oxidative turmoil that results in neuronal death, and for years, the prevailing belief in Alzheimer’s research has been to eliminate it. Thus, there’s a small satisfaction in observing a team from Melbourne take the contrary approach. They intentionally transported copper across the blood-brain barrier, resulting in the improvement of their mice’s brains rather than deterioration.
The mice of interest were ten months old, which corresponds to a sort of middle-aged decline for APP/PS1 mice. These creatures are specifically bred to develop the classic symptoms of human Alzheimer’s: sticky amyloid-beta deposits, the protein fragment that clusters into plaques and stubbornly remains.
In a healthy brain, amyloid does exit, more or less continuously. It gets swept out through the vessel walls and into the bloodstream by molecular pumps situated in the barrier, the most significant of which bears the rather unattractive name P-glycoprotein, or P-gp for short. Consider P-gp as the brain’s sump pump. As long as it operates, the basement stays dry. The difficulty with Alzheimer’s, and part of what renders the disease so brutal, is that it seems to disrupt the very pump designed to relieve it.
As amyloid builds up, P-gp levels diminish. As P-gp diminishes, more amyloid remains. It forms a feedback loop that constricts like a noose.
Repairing the Drain Instead of Mopping the Floor
Jae Pyun, who conducted the research as the concluding element of his PhD at the Monash Institute of Pharmaceutical Sciences, aimed to determine if a specific copper compound could disrupt that cycle. The compound, Cu(ATSM), boasts an intriguing background. It is already undergoing human trials for Parkinson’s and motor neuron disease, has passed safety evaluations, and crosses the blood-brain barrier relatively easily, unlike most molecules typically targeted for brain entry.
For 56 days, the team administered a daily dose of 30 milligrams per kilogram to the mice, then measured the results. The findings narrate a cohesive story. Copper levels in the brain’s microvessels surged significantly. The quantity of P-gp at the barrier increased by just over 24 percent. Furthermore, the toxic, human variant of amyloid-beta in the cortex, specifically the fragment known as Aβ42 that causes the most harm, declined by 42 percent.
“This is the first study to demonstrate that Cu(ATSM) can enhance the abundance of P-gp clearance pumps in an Alzheimer’s model by 24.1 percent, effectively connecting the restoration of the blood-brain barrier to a decrease in toxic proteins and enhanced cognitive function,” states Pyun. That final clause holds particular significance. Reducing amyloid is the primary objective of every approved Alzheimer’s medication to date; what sets this apart is the approach. Instead of directly mopping up plaques from the brain tissue, as antibody drugs do, Cu(ATSM) appears to have repaired the drain.
Whether the mice perceived this change is a different matter, and the one Pyun was most eager to address. The team utilized the Barnes maze, a circular platform riddled with holes, only one of which leads to a dark, safe escape box beneath. A mouse with intact spatial memory learns the location of the exit and heads directly towards it. A mouse with diminishing memory wanders aimlessly. After treatment, the APP/PS1 mice navigated the maze and recalled it significantly better than their untreated counterparts, showing nearly a 44 percent improvement in long-term spatial memory. The repaired plumbing appeared to translate into enhanced cognitive abilities.
A Drug With a Head Start, and the Usual Caveat
There’s a disclaimer worth articulating clearly, one that looms over nearly every optimistic Alzheimer’s announcement. This study involved mice, specifically a strain designed to model a rare inherited form of the disease, and the track record of dementia research is littered with compounds that restored memory in mice yet produced no effects in humans. The jump from a Barnes maze to a human existence is substantial.
What provides Joseph Nicolazzo, the senior author who leads Monash’s Centre for Drug Candidate Optimisation, with some basis for hope is the head start. Since the compound has already completed human safety testing for other neurodegenerative disorders, it could theoretically transition into Alzheimer’s trials more rapidly than a completely new molecule. “Because reducing amyloid burden is clinically proven to enhance functional outcomes,” Nicolazzo states, “these preclinical outcomes strongly support the rationale for testing this drug in early symptomatic Alzheimer’s disease.” The researchers also suspect the copper may serve an additional role, stimulating the brain’s resident immune cells, the microglia, to engulf the plaques themselves, potentially tackling the disease from two angles simultaneously.