The cellular 'hitchhiking' that could explain the advance of Alzheimer's

BarcelonaAlzheimer's disease probably does not have a single cause. For this reason, the scientific community continues to study the changes that occur in the brains of affected people to determine if they are the origin of the disease or a consequence of the neurodegenerative process. Currently, two hypotheses concentrate a good part of the research. The first, dominant for decades, points to the accumulation of beta-amyloid plaques, deposits of protein fragments that accumulate between neurons. The second focuses on the Tau protein, which forms aggregates within neurons in the form of tangles and is associated with neuronal death. A study published this Monday in the journal Cell by the University of Utah Health —with the support of the National Institutes of Health (NIH) of the United States— delves into this second hypothesis. The work indicates that a brain protein called Arc can facilitate the spread of Tau from diseased neurons to healthy neurons.

Led by neurobiology professor Jason Shepherd, researchers at the University of Utah Health have discovered, in mice, that Arc is necessary for toxic Tau to spread. Normally, Arc acts as an essential messenger between brain cells: it wraps itself inside a microscopic bubble, called an extracellular vesicle, which moves from one neuron to another carrying important information. But this natural function can be altered by toxic Tau, which can adhere to it to take advantage of the transport and pass from a diseased neuron to a healthy one. As if it were hitchhiking and waiting for a car to take it to the other side of the brain. Although all neurons contain Tau, in Alzheimer's disease it begins to clump together, forming large sticky tangles inside neurons, which ultimately causes cell death.

"Tau tangles stick to each other and block transport within the neuron. But they can break down into sticky little monsters, called Tau seeds, which can then be transferred to a new neuron. And when that Tau seed comes into contact with healthy Tau, it's able to corrupt it. Thus, the pathology starts anew in a healthy neuron," posits Mitali Tyagi, a postdoctoral researcher at Washington University in St. Louis and first author of the paper while a neuroscience graduate student in Shepherd's lab. If therapies could be developed to target this spread, they could become a powerful tool to stop Alzheimer's disease from progressing, the researchers propose.

To test their hypothesis, the team used mice with Alzheimer's. They observed that extracellular vesicles contained both Arc and "sticky" Tau, and that these small bubbles of Arc and Tau could infect healthy cells and initiate the formation of new Tau tangles. In contrast, in mice with Alzheimer's that did not have the Arc protein, these vesicles contained almost no Tau and could no longer spread the disease to new cells. "When we removed Arc, we observed that Tau transfer was reduced very, very significantly. It had practically disappeared," says Tyagi.

Far from testing it in humans

Given these results, it would be easy to fall into the trap of thinking that blocking Arc could be used to treat Alzheimer's. But, in biology, things are rarely that simple. In the case of Arc, this protein could also play a protective role in the early stages of the disease. By removing excess toxic Tau, Arc seems to help diseased cells stay alive for longer. Researchers observed that, in mice lacking the protein and therefore unable to expel toxic Tau from diseased cells, these cells die more quickly.

"When Arc is absent, Tau gets trapped inside neurons and accumulates to toxic levels. When Arc is present, Tau can be released via extracellular vesicles. While this helps reduce Tau accumulation within the original neuron, the released Tau can be taken up by neighboring healthy neurons, thus promoting the spread of pathology," explains Tyagi. This suggests that a potentially more effective therapeutic strategy would be to prevent toxic Tau from entering healthy cells rather than preventing its release from diseased cells.

However, these results were obtained in mice. Researchers also found extracellular vesicles containing both Arc and Tau in human brain tissue, suggesting that Tau likely spreads similarly in people. However, much more research is still needed before a therapy can be developed that reaches humans. "But this could open up new avenues for developing a new treatment," says Shepherd. Specifically, he emphasizes, a therapy that can block extracellular vesicles containing toxic Tau "mid-transit," after they have been expelled by diseased cells but before they can infect healthy ones. These therapies would not repair existing brain damage, but they could prevent the disease from continuing to progress. This would mean avoiding further brain damage and additional cognitive decline.