Scientists may have finally found how Alzheimer’s spreads through the brain

Alzheimer's disease is marked by the buildup of a toxic protein called Tau, which damages and eventually kills brain cells. As this harmful protein moves into new areas of the brain, the disease progresses, leading to worsening memory loss and cognitive decline.

Now, researchers have uncovered an unexpected player in that process. In a study of 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 for slowing Alzheimer's disease. Rather than trying to eliminate Tau entirely, future treatments might stop it from reaching healthy brain cells in the first place.

"I'm excited by the fact that we've identified a new way of potentially stopping the progression of Alzheimer's disease," says Jason Shepherd, PhD, professor of neurobiology at University of Utah Health and senior author of the study.

The findings were published in the journal Cell.

How Arc Helps Toxic Tau Travel

To investigate how Alzheimer's spreads, the researchers compared mouse models of the disease with and without the Arc protein. Their experiments showed that Arc is essential for moving toxic Tau between neurons.

Under normal conditions, Arc plays an important role in brain function. The protein packages itself inside tiny membrane bound sacs known as extracellular vesicles (EVs), which travel from one neuron to another carrying important cellular signals.

The researchers found that toxic Tau can exploit this natural communication system. By attaching itself to Arc inside these microscopic vesicles, Tau is able to travel from an unhealthy neuron into a healthy one, where it can continue spreading disease.

Tau Turns Healthy Brain Cells Toxic

Every neuron contains Tau, but in Alzheimer's disease the protein begins clumping into large, sticky tangles that interfere with the cell's internal transport system before eventually killing the neuron.

Mitali Tyagi, PhD, postdoctoral research associate at Washington University in St. Louis and first author of the study, who conducted the research while a neuroscience graduate student in the Shepherd Lab at U of U Health, compares these tangles to "glue monsters."

"They glue together and block transportation within the neuron," Tyagi explains. "But they can break down into smaller glue monsters, called Tau seeds, which can then get transferred to a new neuron. And once this Tau seed comes into contact with healthy Tau, it is able to corrupt it. So, the pathology starts all over again in a healthy neuron."

In the Alzheimer's mouse model, the team found extracellular vesicles containing both Arc and "sticky" Tau in brain tissue. These vesicles were capable of entering healthy cells and triggering the formation of new Tau tangles.

The picture changed dramatically when Arc was removed. Mice lacking the protein had extracellular vesicles containing very little Tau, and the disease could no longer spread effectively to neighboring brain cells.

"When we removed Arc, we saw that the transfer of Tau was severely, severely reduced," Tyagi says. "It was almost gone."

Arc Has Both Harmful and Helpful Effects

Although blocking Arc might sound like an obvious treatment strategy, the researchers discovered that the protein also performs an important protective role during the early stages of 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 those already sick 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 Tau buildup within the original neuron, the released Tau can be taken up by neighboring healthy neurons, promoting the spread of pathology," Tyagi says.

These findings suggest that the most effective treatment may not be preventing diseased cells from releasing Tau. Instead, it may be better to stop those 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 the same mechanism could exist in people. However, they stress that much more research is needed before any potential therapy reaches patients.

"Most of the work we've been doing is in mice, not in humans," Shepherd says. "We have some clues that whatever is happening in these mice could also be happening in humans, but we don't know that yet. And we're far away from saying that we're developing a treatment for anything. But it could open new avenues to get to that point."

One promising possibility would be to intercept Tau containing extracellular vesicles after they leave diseased neurons but before they reach healthy ones. While such an approach would not reverse existing brain damage, it could potentially slow or prevent further spread of Alzheimer's disease.

"If we could target these particular EVs, that would be a really useful therapy strategy," Shepherd says. "For someone with early-onset Alzheimer's or dementia, if we could stop the spread, then we could prevent further damage and cognitive decline."

The study, titled "Arc mediates intercellular tau transmission via extracellular vesicles," was published in Cell.

The research was supported by the National Institutes of Health, including the Director's Office Transformative Research Award (R01 NS115716), the National Institute of Neurological Disorders and Stroke (DSPAN F99), and the National Institute on Aging (AG073236), the Chan-Zuckerberg Initiative Ben Barres Early Acceleration Award, the Alzheimer's Association, the McKnight Brain Disorders Award, the Jon M. Huntsman Presidential Endowed Chair fund, the Max Planck Society, AIRC IG 26229, PRIN 2022EMZJL4, the Rainwater Foundation, the JPB Foundation, and the Cure Alzheimer Fund. The Massachusetts Alzheimer's Disease Research Center, supported by the National Institute on Aging (P30AG062421) provided human samples.

Shepherd is a co-founder of VNV, LLC and holds stock in and is a consultant for Aera Therapeutics, Inc., which licenses intellectual property and patents that include Arc capsids.