Alzheimer’s disease is characterized by the accumulation of a toxic protein called tau, which damages and eventually kills brain cells. As this harmful protein spreads to new areas of the brain, the disease progresses, leading to increasing memory loss and cognitive decline. Now, researchers have discovered an unexpected player in this process. In a study of mice, they found that a brain protein called Arc—which normally supports communication between nerve cells—also appears to contribute to the spread of toxic tau from diseased brain cells to healthy ones. The discovery points to a potential new strategy for slowing the progression of Alzheimer’s disease. Instead of trying to eliminate tau completely, future treatments could prevent it from reaching healthy brain cells in the first place. The findings were published in the journal *Cell *.
How Arc Helps Transport Toxic Tau
“I’m thrilled that we’ve identified a new way to potentially halt the progression of Alzheimer’s disease,” said Dr. Jason Shepherd, professor of neurobiology at the University of Utah Health and senior author of the study. To investigate how Alzheimer’s disease spreads in the brain, the researchers compared mouse models of the disease with and without the Arc protein. Their findings revealed that Arc plays a crucial role in the transport of toxic tau between nerve cells. Under normal conditions, Arc is an important neuronal protein involved in communication between nerve cells and plays a role in learning and memory processes. It is activated during neuronal activity and helps process and store information within the brain.
A key function of Arc is to incorporate itself into small, membrane-bound vesicles known as extracellular vesicles (EVs). These vesicles serve as a kind of transport vehicle between neurons and facilitate the exchange of proteins, RNA, and other signaling molecules. In this way, they support communication in the brain at the cellular level. The researchers have now been able to show that this natural transport mechanism is hijacked by Alzheimer’s pathology.
In this process, the disease-causing tau protein binds to Arc and is incorporated into the same extracellular vesicles that are normally intended for physiological information exchange. As a result, tau is not degraded within the diseased cell but is actively transported out of it. As soon as these vesicles are taken up by healthy neurons, the toxic tau enters the new cells and can trigger the misfolding of the body’s own tau proteins there. This so-called “prion-like” mechanism causes the pathological protein deposits to gradually spread throughout the brain, affecting increasingly larger neural networks.
What is particularly significant here is that Arc itself originally has a protective function, as it helps cells remove excess or harmful amounts of protein. In this case, however, this otherwise useful disposal and communication pathway becomes a vulnerability, as it allows the toxic tau to spread effectively between neurons. The researchers were also able to show that this process is significantly reduced or nearly completely prevented when Arc is absent in the models, underscoring the central role of this protein in the disease’s spread mechanism.
Tau Makes Healthy Brain Cells Toxic
Every neuron contains tau, but in Alzheimer’s disease, the protein begins to aggregate into large, sticky clumps that disrupt the cell’s internal transport system before eventually killing the neuron. Mitali Tyagi, PhD, a postdoctoral fellow at Washington University in St. Louis and first author of the study—who conducted the research during her doctoral studies in neuroscience in the Shepherd Lab at U of U Health—compares these clumps to “glue monsters.” “They stick together and block transport within the neuron,” explains Tyagi. “However, they can break down into smaller ‘glue monsters,’ known as tau seeds, which can then be transferred to a new neuron. As soon as this tau seed comes into contact with healthy tau, it can damage it. This is how the pathological process starts all over again in a healthy neuron.”
In a mouse model of Alzheimer’s disease, the team found extracellular vesicles in the brain tissue that contained both Arc and “sticky” tau. These vesicles were able to penetrate healthy cells and trigger the formation of new tau clumps. The picture 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 found that tau transmission was extremely reduced,” said Tyagi. “It had almost completely disappeared.”
Arc Has Both Harmful and Beneficial Effects
Although blocking Arc may sound like an obvious treatment strategy, the researchers discovered that the protein also plays an important protective role in the early stages of the disease.By helping neurons excrete excess toxic tau, Arc appears to enable damaged cells to survive longer. In mice lacking Arc, toxic tau remained trapped inside the neurons, causing these already diseased cells to die off more quickly.
When Arc is absent, tau becomes trapped within the neurons and accumulates to toxic levels. When Arc is present, tau can be released into extracellular vesicles. While this helps reduce tau accumulation in the original neuron, the released tau can be taken up by neighboring healthy neurons, thereby promoting the spread of the pathology.
These findings suggest that the most effective treatment may not be to prevent diseased cells from releasing tau. Instead, it might 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 both Arc and tau in human brain tissue, suggesting that the same mechanism might exist in humans. However, they emphasize that much more research is needed before a potential therapy can reach patients.
“Most of our work so far has been conducted in mice, not in humans,” said Shepherd. “We have some evidence that what’s happening in these mice could also happen in humans, but we don’t know that yet. And we’re still a long way from being able to say that we’re developing a treatment for anything. But it could open up new avenues for getting there.” A promising therapeutic strategy could therefore involve specifically preventing the spread of tau-containing extracellular vesicles before they reach healthy nerve cells and trigger new pathological protein deposits there. Since these vesicles apparently play a central role in “spreading” the pathology, it would be conceivable to either intercept them in the extracellular space, block their uptake into healthy neurons, or influence their formation within the diseased cells themselves.
Such approaches would not aim to reverse damage that has already occurred in the brain, but rather to slow the progression of the disease or, in the best-case scenario, halt it. In Alzheimer’s disease in particular, the timing of intervention is considered crucial, as irreversible neuronal damage occurs early in the course of the disease and cannot be repaired later. Intervening in the mechanisms by which tau spreads could therefore have clinically relevant benefits, particularly in the early stages of the disease. At the same time, the researchers emphasize that the findings to date are primarily based on animal models, and it remains unclear to what extent this mechanism functions exactly the same way in humans. Nevertheless, the identification of Arc-mediated vesicle transport opens up new avenues for future medications, such as antibodies that specifically bind to tau-laden vesicles, or molecular inhibitors that specifically prevent the release or uptake of these vesicles. In the long term, this could lead to therapies that not only treat symptoms but also directly intervene in the disease-causing spread of the disease, thereby significantly slowing cognitive decline in Alzheimer’s patients.