Researchers at the University of California, Riverside have proposed a new explanation for how Alzheimer’s disease may begin. Instead of being driven primarily by plaque buildup in the brain, the disease could start when one protein interferes with the normal function of another inside nerve cells.
For years, Alzheimer’s research has largely centered on amyloid beta (a-beta), a protein that forms clumps in the brains of people with the disease. The idea gained support because inherited mutations that increase a-beta levels can cause early onset Alzheimer’s.
However, despite thousands of clinical trials designed to remove a-beta, those treatments have largely failed to stop the disease or reverse its progression.
Scientists have also long known that another protein called tau accumulates in the brains of Alzheimer’s patients. What has remained uncertain is exactly how tau and a-beta are connected.
“In addition to having dementia, Alzheimer’s diagnosis requires both a-beta and tau buildup in the brain,” said UCR chemistry professor and study lead author Ryan Julian. “But many labs focus on the role of one and ignore the other.”
Published in the Proceedings of the National Academy of Sciences, Nexus, the new study points to a direct interaction between these two proteins.
How Amyloid Beta and Tau May Interact
Tau normally helps stabilize microscopic structures known as microtubules. These tiny tube-like structures act as transportation routes inside nerve cells, carrying essential materials to different parts of the neuron. Without functioning microtubules, neurons struggle to transport the molecules they need to survive and communicate.
The research team noticed that the section of tau responsible for attaching to microtubules closely resembles a-beta in both size and structure. That observation led them to wonder whether a-beta could also bind to microtubules.
To investigate, the scientists attached a fluorescent marker to a-beta. By tracking changes in its movement and light emission, they were able to determine when the protein attached itself to microtubules.
Their experiments revealed that a-beta and tau bind to microtubules with similar strength. As a result, when a-beta accumulates inside neurons, it can potentially push tau out of its normal position.
“Our work shows amyloid beta and tau compete for the same binding sites on microtubules, and that a-beta can prevent tau from functioning correctly,” Julian said.
A New Possible Trigger for Alzheimer’s
According to the researchers, Alzheimer’s may begin when a-beta displaces tau from microtubules. Once that happens, the cell’s internal transport network may start to break down.
At the same time, tau may begin behaving abnormally. Without its normal interaction with microtubules, the protein can clump together and move into regions of neurons where it does not normally belong.
This model suggests that the buildup of a-beta and tau may be a consequence of deeper cellular problems rather than the original cause of the disease. The idea could help explain several long-standing puzzles in Alzheimer’s research.
For example, plaques made of a-beta often form outside cells. If the key damage occurs when a-beta interferes with tau inside neurons, those external plaques may not directly disrupt tau or the microtubules it supports.
Aging, Autophagy, and Microtubules
The proposed mechanism also fits with evidence that the brain’s natural recycling process becomes less efficient with age.
A process known as autophagy normally removes unwanted proteins, including a-beta, from cells. As autophagy slows in older adults, a-beta may accumulate inside neurons and increasingly compete with tau for access to microtubules.
Additional observations support the theory as well. Some recent studies have reported that lithium may reduce the risk of Alzheimer’s disease, while earlier research found that lithium helps stabilize microtubules.
Those findings raise the possibility that protecting microtubules could help counter some of the harmful effects caused by a-beta.
Implications for Future Treatments
If future studies confirm these results, they could influence the direction of Alzheimer’s drug development.
Rather than focusing exclusively on removing protein clumps, researchers might target the interaction between a-beta and microtubules. Another potential strategy would be boosting the cell’s ability to clear a-beta before it accumulates inside neurons.
Julian believes the findings help tie together many previously disconnected observations from Alzheimer’s research.
“This idea helps make sense of many results that previously seemed unrelated,” Julian said. “It gives us a clearer picture of what may be going wrong inside neurons and where new treatments might start.”
