Alzheimer’s disease is characterized by the buildup of a toxic protein called Tau, which damages and eventually kills brain cells. As this harmful protein reaches new areas of the brain, the disease progresses and worsens memory loss and cognitive decline.
Now, researchers have discovered an unexpected player in that process. In a study with mice, they 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 ones.
The discovery points to a possible new strategy to curb Alzheimer’s disease. Rather than trying to eliminate Tau completely, future treatments could prevent it from reaching healthy brain cells in the first place.
“I’m excited that we’ve identified a new way to potentially stop the progression of Alzheimer’s disease,” said Jason Shepherd, PhD, professor of neurobiology at the University of Utah Health and senior author of the study.
The findings were published in the journal. Cell.
How Arc Helps Toxic Tau Trips
To investigate how Alzheimer’s spreads, researchers compared mouse models of the disease with and without the Arc protein. Their experiments demonstrated that Arc is essential for moving toxic Tau between neurons.
Under normal conditions, Arc plays an important role in brain function. The protein is packaged inside small membrane-bound sacs known as extracellular vesicles (EVs), which travel from one neuron to another carrying important cellular signals.
Researchers discovered that toxic Tau can exploit this natural communication system. By binding to Arc within these microscopic vesicles, Tau can travel from a diseased neuron to a healthy one, where it can continue to spread disease.
Tau turns healthy brain cells into toxic ones
Every neuron contains Tau, but in Alzheimer’s disease the protein begins to clump together into large sticky tangles that interfere with the cell’s internal transport system before eventually killing the neuron.
Mitali Tyagi, PhD, a postdoctoral research associate at Washington University in St. Louis and first author of the study, who conducted the research when she was a neuroscience graduate student in the Shepherd Lab at U of U Health, compares these tangles to “glue monsters.”
“They bind and block transport within the neuron,” explains Tyagi. “But they can break down into smaller sticky monsters, called Tau seeds, which can then be transferred to a new neuron. And once this Tau seed comes into contact with healthy Tau, it can corrupt it. Then the pathology starts again in a healthy neuron.”
In the Alzheimer’s mouse model, the team found extracellular vesicles containing both Arc and “sticky” Tau in the brain tissue. These vesicles were able to enter healthy cells and trigger the formation of new Tau tangles.
The image changed dramatically when Arc was removed. Mice lacking the protein had extracellular vesicles that contained very little Tau, and the disease could no longer spread effectively to neighboring brain cells.
“When we removed Arc, we saw that Tau transfer was greatly reduced,” Tyagi says. “It was almost gone.”
The bow has both harmful and useful effects
Although blocking Arc may seem like an obvious treatment strategy, the researchers found that the protein also plays an important protective role during the early stages of the disease.
By helping neurons expel excess toxic Tau, Arc appears to allow damaged cells to survive longer. In mice without Arc, toxic Tau remained trapped inside neurons, causing already diseased cells to die more quickly.
“When Arc is absent, Tau becomes trapped inside neurons and accumulates to toxic levels. When Arc is present, Tau can be released in extracellular vesicles. While this helps reduce the accumulation of Tau within the original neuron, the released Tau can be taken up by neighboring healthy neurons, promoting the spread of pathology,” says Tyagi.
These findings suggest that the most effective treatment may not be to prevent diseased cells from releasing Tau. Instead, it may be better to prevent these toxic extracellular vesicles from entering healthy neurons.
A potential new target for Alzheimer’s therapies
The researchers also found extracellular vesicles containing Arc and Tau in human brain tissue, suggesting that the same mechanism could exist in people. However, they stress that much more research is needed before any potential therapies reach patients.
“Most of the work we’ve been doing is in mice, not humans,” Shepherd says. “We have some clues that what’s happening in these mice could also be happening in humans, but we don’t know yet. And we’re a long way from saying we’re developing a treatment for anything. But it could open up new avenues to get there.”
A promising possibility would be to intercept extracellular vesicles containing Tau after they leave diseased neurons but before they reach healthy ones. While this approach would not reverse existing brain damage, it could potentially slow or prevent the further spread of Alzheimer’s disease.
“If we could focus on these EVs in particular, that would be a really useful therapeutic strategy,” Shepherd says. “For someone with Alzheimer’s or early-onset dementia, if we could stop the spread, then we could prevent further damage and cognitive decline.”
The study, titled “Arc mediates intercellular transmission of tau via extracellular vesicles,” was published in Cell.
The 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) and the National Institute on Aging (AG073236), the Ben Barres Early Acceleration Award from the Chan-Zuckerberg Initiative, the Alzheimer’s Association, the McKnight Award from Brain Disorders, the Jon M. Huntsman Presidential Chair Fund, the Max Planck Society, AIRC IG 26229, PRIN 2022EMZJL4, Rainwater Foundation, JPB Foundation, and Cure Alzheimer Fund. Human samples were provided by the Massachusetts Alzheimer’s Disease Research Center, with support from the National Institute on Aging (P30AG062421).
Shepherd is a co-founder of VNV, LLC, owns stock in, and is a consultant for Aera Therapeutics, Inc., which licenses intellectual property and patents including Arc capsids.