Key Alzheimer’s proteins are competing inside brain cells
Amyloid beta may disrupt tau’s helpful role
New UC Riverside-led research suggests Alzheimer’s arises not simply from plaques forming in the brain, as is widely believed, but from one protein interfering with the normal job of another.
For decades, much Alzheimer’s research has focused on the idea that clumps of amyloid beta or a-beta proteins cause the disease. Genetic mutations that increase a-beta are known to trigger early onset Alzheimer’s, reinforcing this view.
Yet thousands of clinical trials aimed at removing a-beta have failed to stop or reverse the disease.
Scientists also know that tau protein accumulates in the brains of Alzheimer’s patients. But the exact relationship between tau and a-beta has remained unclear. “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 suggests a direct connection between the two proteins.
Tau’s main function is to stabilize structures inside cells called microtubules. As their name suggests, microtubules are tiny tubes. They function like highways for essential molecules to be transported to different parts of a nerve cell. Without microtubules, neurons cannot properly move materials required for survival and communication.
The researchers noticed that the regions of tau protein that attach to microtubules bear a striking resemblance to the size and structure of a-beta. That similarity raised the possibility that a-beta might also bind to microtubules.
In this study, the researchers tagged a-beta with a fluorescent marker. When its movements slowed down and the light it emitted changed, scientists could see that a-beta had attached to microtubules.
These experiments showed that a-beta and tau bind with roughly the same strength, meaning amyloid beta can displace tau if it accumulates inside neurons.
“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.
These results suggest the disease could begin when a-beta displaces tau, causing the transport system inside nerve cells to start breaking down. Also, when not interacting with microtubules, tau begins to misbehave in other ways and starts to aggregate and migrate into parts of neurons where it doesn’t belong.
By revealing that aggregation of a-beta and tau are downstream effects rather than the primary cause, many inconsistencies in theories about Alzheimer's disease can be reconciled. For example, a-beta plaques that form outside cells might not interfere with the tau inside cells, or the microtubules that tau stabilizes.
The theory also fits with evidence that the brain’s recycling system slows with age. Autophagy normally clears proteins such as a-beta from cells. If that process slows in older adults, a-beta may accumulate and begin competing with tau for microtubule binding.
Other observations also align with the model. Recent studies have shown lithium can lower Alzheimer’s risk, while previous studies found that lithium stabilizes microtubules. This raises the possibility that protecting microtubules could counteract the disruptive effects of a-beta.
If confirmed, the findings could shift the focus of Alzheimer’s therapy. Instead of targeting protein clumps alone, researchers might aim to prevent a-beta from interfering with microtubules or enhance the cell’s ability to remove it from neurons.
Julian said the work helps connect decades of separate Alzheimer’s findings into a single explanation.
“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.”
END
For decades, much Alzheimer’s research has focused on the idea that clumps of amyloid beta or a-beta proteins cause the disease. Genetic mutations that increase a-beta are known to trigger early onset Alzheimer’s, reinforcing this view.
Yet thousands of clinical trials aimed at removing a-beta have failed to stop or reverse the disease.
Scientists also know that tau protein accumulates in the brains of Alzheimer’s patients. But the exact relationship between tau and a-beta has remained unclear. “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 suggests a direct connection between the two proteins.
Tau’s main function is to stabilize structures inside cells called microtubules. As their name suggests, microtubules are tiny tubes. They function like highways for essential molecules to be transported to different parts of a nerve cell. Without microtubules, neurons cannot properly move materials required for survival and communication.
The researchers noticed that the regions of tau protein that attach to microtubules bear a striking resemblance to the size and structure of a-beta. That similarity raised the possibility that a-beta might also bind to microtubules.
In this study, the researchers tagged a-beta with a fluorescent marker. When its movements slowed down and the light it emitted changed, scientists could see that a-beta had attached to microtubules.
These experiments showed that a-beta and tau bind with roughly the same strength, meaning amyloid beta can displace tau if it accumulates inside neurons.
“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.
These results suggest the disease could begin when a-beta displaces tau, causing the transport system inside nerve cells to start breaking down. Also, when not interacting with microtubules, tau begins to misbehave in other ways and starts to aggregate and migrate into parts of neurons where it doesn’t belong.
By revealing that aggregation of a-beta and tau are downstream effects rather than the primary cause, many inconsistencies in theories about Alzheimer's disease can be reconciled. For example, a-beta plaques that form outside cells might not interfere with the tau inside cells, or the microtubules that tau stabilizes.
The theory also fits with evidence that the brain’s recycling system slows with age. Autophagy normally clears proteins such as a-beta from cells. If that process slows in older adults, a-beta may accumulate and begin competing with tau for microtubule binding.
Other observations also align with the model. Recent studies have shown lithium can lower Alzheimer’s risk, while previous studies found that lithium stabilizes microtubules. This raises the possibility that protecting microtubules could counteract the disruptive effects of a-beta.
If confirmed, the findings could shift the focus of Alzheimer’s therapy. Instead of targeting protein clumps alone, researchers might aim to prevent a-beta from interfering with microtubules or enhance the cell’s ability to remove it from neurons.
Julian said the work helps connect decades of separate Alzheimer’s findings into a single explanation.
“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.”
END