Most copper in the brain is a problem. It piles up in the wrong places, drives the oxidative chaos that kills neurons, and for years the going wisdom in Alzheimer’s research has been to strip it out. So there’s a small pleasure in watching a team from Melbourne do the opposite. They ferried copper deliberately across the blood-brain barrier, and the brains of their mice got better rather than worse.
The mice in question were ten months old, which for an APP/PS1 mouse is a kind of middle-aged decline. These animals are bred to develop the hallmark of human Alzheimer’s: sticky deposits of amyloid-beta, the protein fragment that clumps into plaques and refuses to leave.
In a healthy brain, amyloid does leave, more or less constantly. It gets bundled out through the vessel walls and into the bloodstream by molecular pumps embedded in the barrier, the most important of which goes by the rather unlovely name P-glycoprotein, or P-gp for short. Think of P-gp as the brain’s sump pump. As long as it runs, the basement stays dry. The trouble with Alzheimer’s, and part of what makes the disease so vicious, is that it appears to break the very pump meant to bail it out.
As amyloid accumulates, P-gp numbers fall. As P-gp falls, more amyloid stays put. It’s a feedback loop that tightens like a noose.
Fixing the Drain Instead of Mopping the Floor
Jae Pyun, who carried out the work as the final piece of his PhD at the Monash Institute of Pharmaceutical Sciences, wanted to know whether a particular copper compound could break that loop. The compound, Cu(ATSM), has an interesting pedigree. It is already in human trials for Parkinson’s and motor neurone disease, has cleared safety hurdles, and slips across the blood-brain barrier without much difficulty, which is more than can be said for most molecules anyone has ever wanted to put into a brain.
For 56 days the team gave the mice a daily dose, 30 milligrams per kilogram, then counted what was left. The numbers tell a tidy story. Copper in the brain’s microvessels rose sharply. The abundance of P-gp at the barrier climbed by just over 24 per cent. And the toxic, human form of amyloid-beta in the cortex, the fragment called Aβ42 that does the most damage, dropped by 42 per cent.
“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,” says Pyun. That last clause is the one that matters. Lowering amyloid is the single thing every approved Alzheimer’s drug to date has been built to do; what differs here is the route. Rather than mopping plaques out of the brain tissue directly, as the antibody drugs do, Cu(ATSM) seems to have fixed the drain.
Whether the mice noticed is a separate question, and the one Pyun was keenest to answer. The team turned to the Barnes maze, a circular platform pocked with holes, only one of which leads to a dark, safe escape box underneath. A mouse with intact spatial memory learns where the exit is and heads straight for it. A mouse with a fading memory wanders. After treatment, the APP/PS1 mice learned the maze and remembered it markedly better than their untreated littermates, an improvement of nearly 44 per cent in long-term spatial memory. The repaired plumbing, it seemed, translated into a sharper mind.
A Drug With a Head Start, and the Usual Caveat
There’s a caution worth stating plainly, the one that shadows almost every hopeful Alzheimer’s headline. This was a study in mice, in a strain engineered to model a rare inherited form of the disease, and the history of dementia research is something of a graveyard of compounds that rescued mouse memory and then did nothing whatsoever for people. The leap from a Barnes maze to a human life is enormous.
What gives Joseph Nicolazzo, the senior author who directs Monash’s Centre for Drug Candidate Optimisation, some grounds for optimism is the head start. Because the compound has already been through human safety testing for other neurodegenerative conditions, it could in principle move into Alzheimer’s trials faster than a molecule starting from scratch. “Because reducing amyloid burden is clinically proven to improve functional outcomes,” Nicolazzo says, “these preclinical results strongly support the rationale for testing this drug in early symptomatic Alzheimer’s disease.” The researchers also suspect the copper may be doing a second job, rousing the brain’s resident immune cells, the microglia, to engulf the plaques themselves, which would mean hitting the disease from two directions at once. Mapping those exit routes is the next task.
It’s hard not to find something fitting in the mechanism. For decades copper has been cast as a villain in the brain, a metal to be chelated and removed. Here it arrives as a delivery, a small package of the very element that, in the right place and the right amount, helps the brain take out its own rubbish. The dose, as the old toxicologists liked to say, makes the poison. In Australia, where dementia has now overtaken heart disease as the leading cause of death, the question of whether that logic holds in people is no longer academic.
DOI / Source: https://doi.org/10.1021/acschemneuro.6c00252
Frequently Asked Questions
Isn’t copper supposed to be bad for the brain in Alzheimer’s?
In the wrong places, yes: loose copper drives the oxidative damage that harms neurons, which is why much of the field has focused on removing it. This study flips that logic by delivering copper in a controlled form, Cu(ATSM), that releases its cargo where the tissue chemistry calls for it. The effect was a repaired waste-clearance system rather than added damage, a reminder that with metals, dose and location are everything.
How does fixing a pump actually reduce toxic proteins?
A transporter called P-glycoprotein normally bails amyloid-beta out of the brain through the blood vessel walls, but in Alzheimer’s its numbers fall and the waste backs up. Cu(ATSM) raised P-gp abundance by about 24 per cent in treated mice, and cortical levels of the toxic Aβ42 fragment dropped by 42 per cent. Restoring the clearance machinery, in other words, let the brain flush out what it could no longer remove on its own.
Could this lead to a human Alzheimer’s treatment soon?
It has a genuine head start, because Cu(ATSM) has already passed safety testing in human trials for Parkinson’s and motor neurone disease, so it could be redirected faster than a brand-new molecule. The large caveat is that these results are in mice bred to model a rare inherited form of the disease, and many compounds that rescued mouse memory have failed in people. Whether the benefit survives that leap is exactly what early human trials would need to establish.
Is repairing the pump the only thing the copper does?
Probably not. Alongside restoring P-gp, the researchers suspect the copper may also rouse the brain’s resident immune cells, the microglia, to engulf and digest amyloid plaques directly. If both routes are real, the drug would be clearing the drain and sending in the cleaners at the same time, which is part of what the team plans to map next.
