Alzheimer’s disease is characterized by the buildup of a toxic protein called tau that damages and eventually destroys brain cells. The disease progresses as this harmful protein moves to new areas of the brain, worsening memory loss and cognitive decline.
This time, researchers discovered an unexpected person in the process. A study in mice found that a brain protein called Arc, which normally helps neurons communicate, also appears to help toxic tau spread from diseased brain cells to healthy brain cells.
The findings suggest a potential new strategy to slow Alzheimer’s disease. Rather than trying to eliminate tau completely, future treatments may block it from reaching healthy brain cells in the first place.
“We are excited by the fact that we have identified a new way to potentially halt the progression of Alzheimer’s disease,” says Dr. Jason Shepherd, professor of neurobiology at the University of Utah Health and senior author of the study.
The research results were published in a magazine cell.
How Ark Helps Transport Toxic Tau
To investigate how Alzheimer’s disease spreads, researchers compared mouse models of the disease that contain the Arc protein with those that do not. Their experiments showed that Arc is essential for moving toxic tau between neurons.
Under normal conditions, Arc plays an important role in brain function. This protein is packaged in small membrane-bound sacs known as extracellular vesicles (EVs) and travels from one neuron to another, transmitting important cellular signals.
Researchers have discovered that toxic tau can exploit this natural communication system. By binding to arcs within these microscopic vesicles, tau can move from unhealthy neurons to healthy neurons, where it can continue to spread the disease.
Tau turns healthy brain cells toxic
All neurons contain tau, but in Alzheimer’s disease, the protein begins to clump together into large sticky tangles that interfere with the cell’s internal transport systems before ultimately killing the neuron.
Dr. Mitali Tyagi, a postdoctoral fellow at Washington University in St. Louis and lead author of the study, who conducted the study while a neuroscience graduate student in Shepard’s lab at U of U Health, likens these tangles to “glue monsters.”
“They adhere to each other and block transport within the neuron,” Tyagi explains. “But they can be broken down into little glue monsters called tau seeds, which can then be transferred to new neurons. And when this tau seed comes into contact with healthy tau, it can destroy it, meaning the pathology starts all over again in the healthy neurons.”
In a mouse model of Alzheimer’s disease, the research team found extracellular vesicles containing both Arc and “sticky” tau in brain tissue. These vesicles were able to enter healthy cells and trigger the formation of new tau tangles.
Once Arc was removed, things changed dramatically. The extracellular vesicles of mice lacking this protein contained little tau, and the disease was unable to spread effectively to neighboring brain cells.
“When we removed the arc, we found that tau migration was significantly reduced,” Tighe said. “It’s almost gone.”
Vape has both harmful and beneficial effects
Although blocking Arc may seem like an obvious therapeutic strategy, researchers have discovered that this protein also plays an important protective role in the early stages of the disease.
Arc appears to help damaged cells survive longer by helping neurons excrete excess toxic tau. In mice without Arc, toxic tau remained trapped inside neurons, causing already diseased cells to die faster.
“In the absence of Arc, tau becomes trapped within neurons and accumulates to toxic levels. When Arc is present, tau can be released within extracellular vesicles. This helps reduce tau accumulation within the original neuron, but the released tau can be taken up by neighboring healthy neurons and promote the spread of the disease,” Tyagi says.
These findings suggest that the most effective treatment may not be to prevent diseased cells from releasing tau. Instead, it may be better to block toxic extracellular vesicles from entering healthy neurons.
Potential new target for Alzheimer’s disease treatment
The researchers also found extracellular vesicles containing both Arc and Tau in human brain tissue, suggesting that the same mechanism may exist in humans. But they stress that more research is needed before potential treatments reach patients.
“Most of the research we’ve done has been in mice, not humans,” Shepard says. “There are some clues that everything that’s happening in these mice might also be happening in humans, but we don’t know that yet. And we’re a long way from saying we’re developing any treatments. But it could open up new avenues to get us to that point.”
One promising possibility is to trap tau containing extracellular vesicles after they leave diseased neurons but before they reach healthy neurons. Although such approaches cannot reverse existing brain damage, they may be able to slow or prevent the further spread of Alzheimer’s disease.
“If we could target these specific electric vehicles, that would be a very useful therapeutic strategy,” Shepherd says. “For people with early-onset Alzheimer’s disease and dementia, stopping the spread could prevent further damage and cognitive decline.”
The study, titled “Arc mediates intercellular tau transmission via extracellular vesicles,” cell.
This research was supported by the National Institutes of Health, including the Office of the Director’s Transformative Research Award (R01 NS115716), the National Institute of Neurological Disorders and Stroke (DSPAN F99), the National Institute on Aging (AG073236), the Chan Zuckerberg Initiative Ben Barres Early Acceleration Award, the Alzheimer’s Association, the McKnight Brain Disorders Award, and the John Award. M. Huntsman Presidential Endowment Chairman’s Fund, Max Planck Society, AIRC IG 26229, PRIN 2022EMZJL4, Rainwater Foundation, JPB Foundation, and Alzheimer’s Treatment Fund. The Massachusetts Alzheimer’s Disease Research Center provided human samples with support from the National Institute on Aging (P30AG062421).
Mr. Shepherd is a co-founder of VNV, LLC, holds an interest in, and is a consultant to Aera Therapeutics, Inc., which licenses intellectual property and patents including Arc Capsid.
