For years, scientists knew that Alzheimer's disease spreads through the brain — but not exactly how. Now, researchers at University of Utah Health have identified the mechanism: a brain protein called Arc acts as a carrier, packaging toxic Tau proteins into microscopic bubbles and delivering them from sick neurons to healthy ones.
The study, published June 29 in the journal Cell, reveals that Arc — which normally serves as a vital messenger between brain cells, wrapping itself in extracellular vesicles (EVs) to carry important information — can be hijacked by toxic Tau. The misfolded Tau protein sticks to Arc and hitches a ride, spreading pathology through the brain.
"I'm excited by the fact that we've identified a new way of potentially stopping the progression of Alzheimer's disease," said Jason Shepherd, professor of neurobiology at U of U Health and senior author on the study.
The research team studied a mouse model of Alzheimer's disease both with and without the Arc protein. In mice with Arc, they found EVs containing both Arc and sticky Tau within the brain — tiny bubbles that could infect healthy cells and start new Tau tangles. But in Alzheimer's model mice that lacked Arc, the brain EVs contained barely any Tau and could no longer spread the disease to new cells.
"When we removed Arc, we saw that the transfer of Tau was severely, severely reduced. It was almost gone," said first author Mitali Tyagi, now a postdoctoral researcher at Washington University in St. Louis.
However, the researchers discovered a double-edged sword: Arc may also play a protective role in early disease stages by helping sick cells eject excess toxic Tau to stay alive longer. In mice that lacked Arc, sick cells died faster because Tau became trapped inside.
This suggests that the most effective therapeutic strategy might be to intercept toxic Tau-carrying EVs "mid-flight" — after they leave sick cells but before they reach healthy ones. The team confirmed that human brain tissue also contains EVs with both Arc and Tau, suggesting a similar mechanism in people.
"If we could target these particular EVs, that would be a really useful therapy strategy," Shepherd said. "For someone with early-onset Alzheimer's or dementia, if we could stop the spread, then we could prevent further damage and cognitive decline."
