A New Study Helps Untangle the Role of Tau in Dementia

The human brain is an incredible, complex web of connections. Cells called neurons send signals from region to region, and their communication allows us to do everything from forming thoughts to accessing memories.

But for nearly 6 million Americans, neurodegenerative diseases like dementia, chronic traumatic encephalopathy (CTE), and Alzheimer’s disease prevent neurons from functioning properly. The progressive memory loss that characterizes these diseases is well-known. Yet the mechanisms that cause them—and ways to treat them—are still poorly understood. That’s partly because neurodegenerative diseases have different causes. CTE can be triggered by repeated head trauma, while fronto-temporal dementia is caused by a genetic mutation, and Alzheimer’s can be triggered by environmental, genetic, and behavioral factors. But all of these diseases are characterized by malfunctions in two proteins found in neurons: beta-amyloid and tau.

Now, scientists are starting to understand more about how tau could trigger and spread disease. In a paper published last week in Cell, researchers at the Buck Institute for Research on Aging detailed the “interactome” of tau, showing all the proteins it comes into contact with. That information offers new insights about how dysfunctional tau affects the cell and how it can travel from neuron to neuron, possibly seeding disease throughout the brain.

“These kinds of studies give us insight into the disease process at the molecular level,” says Tara Tracy, an assistant professor at the Buck Institute and lead author on the paper. “That's the goal with all of these studies, to get more information for things that could be targeted to slow progression.”

For the last several decades, scientists have focused on beta-amyloid, which forms clumps around the outside of cells and blocks communication between them. The theory was that if scientists could find a way to bust those clumps apart—or keep them from appearing in the first place—then the disease could be kept in check.

But after years of development, a number of drugs aimed at beta-amyloid have largely failed to improve patient outcomes. Last year the US Food and Drug Administration granted accelerated approval for Aduhelm, the first such treatment approved since 2003, but it is extremely expensive and has been criticized by doctors who say it’s ineffective at halting the progression of the disease. Many large health systems, including Massachusetts General Hospital, the Cleveland Clinic, and the Department of Veterans’ Affairs, won’t prescribe it.

Concentrating on other proteins involved in neurodegenerative diseases could help scientists find new ways to treat them. “Proteins don’t act in isolation,” says Nicholas Seyfried, an associate professor of biochemistry and neurology at Emory University who studies neurodegeneration. He says the more scientists understand how these malfunctioning proteins affect cells, the more therapeutic options there could be.

What causes tau to transition from a normal protein to a diseased one is sometimes a mystery. For patients with frontotemporal dementia, this is caused by a genetic mutation. But for people with other diseases, the reason tau starts to misbehave is still unknown. In cases of CTE, it may be the consequence of repeated head trauma. In Alzheimer’s disease, environmental factors like air pollution or vascular problems that prevent blood from flowing to the brain may play a role. No matter what the trigger is, eventually the diseased tau proteins will create clumps. Unlike beta-amyloid, these gum up the inside of neurons.

But in her new paper, Tracy suggests that diseased tau is causing trouble by doing more than clinging to itself to create these clusters. It is also changing which other proteins in the cell it interacts with.

To show this, first Tracy and her team had to examine what healthy tau is doing in the cell before and after a neuron fires. It would be too invasive to directly observe what’s happening inside a living human brain, so the team used petri dishes of neurons that were grown from human pluripotent stem cells. They attached a protein called ascorbic acid peroxidase, or APEX, to each end of the tau proteins in the neurons. This acted a bit like a tracking device. Whenever other proteins in the cell got close to the tau, the APEX would rub off on them, the way someone who leans up against a freshly painted wall walks away with a smear on their clothing. That allowed the researchers to look at every single interaction that particular tau protein had. And because they had tagged both ends of it, they could clearly see where the tau was binding with those proteins and whether those interactions happened before or after the neuron fired.

They found that tau is involved in a number of important cellular activities. “It's actually way more complicated than just a protein that forms tangles,” says Tracy. Tau helps maintain the structure of the cell wall. It interacts with more than 30 mitochondrial proteins that help create the energy the cell needs to survive and to send signals. And it comes into contact with presynaptic vesicles, tiny sacs that hold chemical neurotransmitters. When the neuron is triggered, those sacs open and release the neurotransmitters, sending molecular messages out of the cell to other neurons.

Next, the researchers used the same approach, but this time they used neurons in which the tau had the same genetic mutation that causes frontotemporal dementia. They discovered that the mutated proteins affect how the cell works even before they form the tangles that have become the hallmarks of advanced neurodegenerative disease. Diseased tau had fewer interactions than its healthy counterpart, especially with the mitochondrial proteins responsible for powering the cell. That could mean that these proteins are affecting the cell’s metabolism and whether it has enough energy to function properly.

Tracy’s team wanted to make sure that what they were seeing in a petri dish corresponded to how neurodegenerative disease presents in people. So they next examined postmortem brain tissue from patients with diseases that included frontotemporal dementia, Alzheimer’s, and CTE. In these samples, they found that of the more than 30 mitochondrial proteins that interact with tau, 14 were down-regulated, meaning the genes that control these proteins were making fewer of them. Tracy says it’s an indirect relationship, but it does suggest that neurons with diseased tau aren’t getting as much energy from their mitochondria as ones with healthy tau.

“They’ve gone the extra mile to make sure that their model system in cell culture is reflected in the human pathology of disease,” says Meaghan Morris, an assistant professor of pathology at Johns Hopkins University School of Medicine, who studies tau and its role in neurodegenerative disease. It’s interesting, she says, that this pathology was the same for all of the diseases the researchers studied, even though the causes of each are unique.

Translating lab findings like these into drugs that might help people is frustratingly hard. While researchers can use scans and cognitive tests, they can’t directly examine the brains of living patients because there’s no way to do that safely. Researchers often have to rely on postmortem tissues and lab animals, like mice, that serve as proxies—although what works in other animals does not always work in people.

Still, these findings hint at two potentially important ideas for interventions. One has to do with how tau hitches a ride on neurotransmitters, allowing dysfunctional proteins to get out of their own cells and travel to other regions of the brain. "I think it would be great to design a strategy to prevent tau associating with vesicles to slow tau spreading," Tracy says, pointing to other work that suggests this as a method to stop neurodegeneration from advancing.

The mitochondrial results are more complicated, but equally intriguing. Diseased tau seems to affect how much energy the cell produces, but it’s not clear exactly how it does that—or how a drug could be designed to restore normal function. “The biggest surprising factor coming out of this for me is the number of mitochondrial interactions tau has,” says Morris. “That’s really fairly novel, and I hope that gets picked up and pursued because we know that mitochondria are critical to neuron function.”

The study suggests that those 14 down-regulated mitochondrial proteins could be good targets, but Tracy says it’s not clear which ones to investigate. “The challenge with the mitochondrial proteins is that we identified so many of them,” she says. “Which one do you choose?”

What the new study makes clear is that because unhealthy tau affects cellular function even before forming tangles, any future treatment must be delivered as early as possible. “People may be receiving treatments too late,” says Tracy. Better diagnostic tools might help, she suggests, like being able to screen for the DNA mutation that causes frontotemporal dementia. For other neurodegenerative diseases, tests for dysfunctional tau in a person’s blood or spinal fluid could signal who’s at risk.

Still, says Seyfried, there’s probably never going to be one miracle drug that cures every neurodegenerative disease in every patient. Alzheimer’s disease alone will probably require lots of different treatments. “This disease is going to be multifactorial, and there’s going to have to be more than one target,” he says.

Tracy agrees and compares the future of treating neurodegenerative diseases to cancer treatments that can be combined and tailored to each patient’s needs. Multiple options might allow doctors to create treatment plans that target tau, beta-amyloid and other causes, rather than focusing on a one-size-fits-all strategy. “We need a variety of approaches,” she says. “I don't think that there's going to be one thing that cures Alzheimer's.”