Manganese is not a metal most people think much about. Unlike lead or mercury, it has a benign reputation. Small amounts of manganese power enzymes, metabolize nutrients and keep the brain running smoothly. But it's toxic to the brain in excess, producing tremors, muscle stiffness and cognitive decline.
A new Cornell study offers fresh clues to how to remove manganese from the brain, identifying a protein that's critical in flushing it out. The finding could have major implications for welders, miners and people living near industrial sites, as well as people with rare genetic mutations that disrupt how the body handles the metal.
"The brain has ways to protect itself from toxic buildup, but we haven't fully understood how that works," said Tolunay Beker Aydemir, assistant professor of molecular nutrition in the College of Human Ecology. "Our study identifies a protein that helps clear excess manganese, which is critical because too much of this metal can damage the brain."
This should be important to the general public because in some places, she said, there is a lot of manganese in the drinking water. And there can be high amounts in baby formula, which could be even higher if it's prepared with water that is also high in manganese.
Aydemir is the senior author and her former graduate student Jiaqi Zou is the first author of the study, published in The Journal of Nutrition in April. Their study focuses on ZIP14, a protein embedded in the cells that form the brain's most critical protective boundary.
That boundary - the blood-brain barrier - is a tightly controlled interface where the brain's blood vessels act as a selective filter, allowing nutrients in while keeping pathogens and toxins out. The cells lining these tiny vessels, called endothelial cells, are exquisitely organized, with distinct inner and outer surfaces that face the bloodstream and the brain tissue, respectively. Because these cells are polarized, proteins can have very different roles depending on which side of the cell they occupy.
The Cornell team found that ZIP14 is present on both sides of the cells that line the brain's blood vessels. But when manganese levels rise, the protein becomes more concentrated on the brain-facing side, where it helps move excess manganese out of the brain and into the blood. Rather than acting as an entry point, ZIP14 primarily supports the brain's ability to clear this metal. It's more like the cell shifts more of these transporters to where they're needed most, helping remove manganese when levels get too high.
To see this clearly, the researchers turned to a cutting-edge imaging approach called expansion microscopy, leveraging expertise from the lab of Yuhan Wang, assistant professor of nutritional sciences in Cornell Human Ecology.
"The technology was not developed for this," Aydemir said. "But this collaboration helps answer some very fundamental questions about these very small cells."
The technique works by embedding tissue in a swellable hydrogel that physically expands, Wang said, spreading structures apart to reveal details that would otherwise be invisible.
"The expansion helps to localize these transporters within the thin cells lining the blood-brain barrier," Wang said.
Applied to thin slices of mouse brain, the method allowed the team to pinpoint exactly where ZIP14 sits within the nanoscopic architecture of blood vessel walls, and to watch how its position shifted when the animals were exposed to excess manganese.
Under normal conditions, ZIP14 was distributed across both surfaces of the endothelial cells. But after manganese exposure, the protein migrated, clustering more heavily on the brain-facing side, as if rallying to meet the threat.
It's like the cell is responding to a flood by moving more pumps to the right side of the levee, Aydemir explained.
To test what happens when the system breaks down, the researchers engineered mice lacking ZIP14 specifically in their endothelial cells. These animals accumulated significantly more manganese in the brain, particularly after being exposed to the metal through their noses - a delivery method that mimics how people inhale manganese-contaminated air in occupational settings.
Crucially, removing ZIP14 did not seem to affect how much manganese entered the brain in the first place. What changed was the brain's ability to clear it. The protein's major role, the researchers concluded, is in efflux, not influx - helping clarify how the brain clears manganese.
The mice without the protein also showed a specific cognitive deficit: impaired recognition memory, the kind that lets you remember whether you've seen an object before. Motor function, however, appeared intact, a surprising finding that suggests manganese's damage may depend on which brain regions accumulate the metal, not just how much there is overall.
The findings carry practical implications. Mutations in the ZIP14 gene are already known to cause a rare and devastating childhood disorder involving severe manganese poisoning and movement problems. But even beyond rare genetics, the study points to a broader vulnerability. As industrial and environmental manganese exposure rises globally, knowing how the brain defends itself may eventually inform how doctors think about protecting it.
"We can't only concentrate on how potentially harmful metals get into the brain - we have to think about how to get them out," Aydemir said, adding that data suggests ZIP14 may be an important defense against other metals such as iron, zinc and cadmium.
