Researchers at the University of California, Riverside have proposed a new explanation for how Alzheimer’s disease can begin. Instead of being driven primarily by plaque buildup in the brain, the disease could begin when one protein interferes with the normal function of another within nerve cells.
For years, Alzheimer’s research has largely focused 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 beta levels can cause early-onset Alzheimer’s.
However, despite thousands of clinical trials designed to eliminate 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 remains uncertain is exactly how tau and a-beta are connected.
“In addition to having dementia, the diagnosis of Alzheimer’s requires the accumulation of α-beta and tau in the brain,” said UCR chemistry professor and senior author of the study, Ryan Julian. “But many laboratories focus on the role of one and ignore the other.”
Published in the Proceedings of the National Academy of Sciences, NexusThe 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 small tube-like structures act as transport routes within nerve cells, transporting 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 noted that the section of tau responsible for binding to microtubules closely resembles a-beta in both size and structure. That observation led them to wonder if a-beta could also bind to microtubules.
To investigate, the scientists placed a fluorescent marker on a-beta. By tracking changes in its movement and light emission, they were able to determine when the protein bound to microtubules.
Their experiments revealed that a-beta and tau bind to microtubules with similar strength. As a result, when a-beta accumulates within neurons, it can potentially knock tau out of its normal position.
“Our work shows that amyloid beta and tau compete for the same binding sites on microtubules, and that beta can prevent tau from functioning properly,” Julian said.
A new possible trigger for Alzheimer’s
According to the researchers, Alzheimer’s may begin when beta-beta displaces tau from microtubules. Once that happens, the cell’s internal transport network can begin to fail.
At the same time, tau may begin to behave abnormally. Without its normal interaction with microtubules, the protein can clump together and move to regions of neurons where it does not normally belong.
This model suggests that the accumulation of a-beta and tau may be a consequence of deeper cellular problems and not the original cause of the disease. The idea could help explain several long-standing puzzles in Alzheimer’s research.
For example, plaques composed of beta-beta often form outside of 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 beta, from cells. As autophagy slows in older adults, beta-beta may accumulate within neurons and increasingly compete with tau for access to microtubules.
Additional observations also support the theory. Some recent studies have reported that lithium may reduce the risk of Alzheimer’s disease, while previous research found that lithium helps stabilize microtubules.
Those findings raise the possibility that protecting microtubules may help counteract some of the harmful effects caused by beta.
Implications for future treatments
If future studies confirm these results, they could influence the direction of Alzheimer’s drug development.
Instead of focusing exclusively on removing groups of proteins, researchers could focus on the interaction between a-beta and microtubules. Another possible strategy would be to increase the cell’s ability to remove beta-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 idea of what may be going wrong inside neurons and where new treatments could begin.”