Researchers at the University of California, Riverside have proposed a new explanation for how Alzheimer’s disease begins. The disease is not primarily caused by plaque buildup in the brain, but may begin when one protein interferes with the normal functioning of another protein in nerve cells.
For many years, research into Alzheimer’s disease has focused primarily on amyloid beta (a-beta), a protein that forms clumps in the brains of Alzheimer’s patients. This idea gained support because genetic mutations that increase alpha-beta levels can cause early-onset Alzheimer’s disease.
However, despite thousands of clinical trials designed to eliminate alpha-beta, these 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 unclear is how tau and alpha-beta are linked.
“Diagnosis of Alzheimer’s disease requires the presence of both alpha-beta and tau accumulation in the brain, in addition to dementia,” said Ryan Julien, professor of chemistry at UCR and lead study author. “But many labs focus on one role and ignore the other.”
Published in Proceedings of the National Academy of Sciences, Nexusnew research points to a direct interaction between these two proteins.
How do amyloid beta and tau interact?
Tau normally helps stabilize fine structures known as microtubules. These small tube-like structures act as transport routes within the neuron, carrying essential substances to different parts of the neuron. When microtubules are dysfunctional, neurons have a hard time transporting the molecules they need for survival and communication.
The researchers noticed that the part of tau responsible for binding to microtubules is very similar to alpha-beta in both size and structure. This observation led them to wonder whether alpha-beta could also bind to microtubules.
To investigate, scientists attached fluorescent markers to alpha-beta. By tracking changes in its movement and luminescence, they were able to pinpoint when the protein attaches to microtubules.
Their experiments revealed that alpha-beta and tau bind to microtubules with similar strength. As a result, when alpha-beta accumulates within neurons, it can push tau out of its normal position.
“Our study shows that amyloid beta and tau compete for the same binding sites on microtubules, and that alpha beta can interfere with tau’s normal function,” Julien said.
Possible new trigger for Alzheimer’s disease
Researchers say Alzheimer’s disease may begin when alpha-beta displaces tau from microtubules. When that happens, the cell’s internal transport network can begin to fail.
At the same time, tau can begin to behave abnormally. Without normal interaction with microtubules, proteins can aggregate and migrate to areas of the neuron to which they normally do not belong.
This model suggests that alpha-beta and tau accumulation may be the result of deeper cellular problems rather than the original cause of the disease. This idea could help explain a long-standing mystery in Alzheimer’s disease research.
For example, plaques made of alpha-beta often form on the outside of cells. If significant damage occurs when alpha-beta interferes with tau inside neurons, those external plaques may not directly destroy tau or the microtubules that tau supports.
Aging, autophagy, microtubules
The proposed mechanism is also consistent with evidence that the brain’s natural recycling processes become less efficient with age.
Normally, a process known as autophagy removes unwanted proteins, including alpha-beta, from cells. As autophagy slows in older adults, alpha-beta may accumulate within neurons and increasingly compete with tau for access to microtubules.
Additional observations also support this theory. Some recent studies have reported that lithium may reduce the risk of Alzheimer’s disease, while previous studies have found that lithium helps stabilize microtubules.
These findings raise the possibility that microtubule protection may help counter some of the deleterious effects caused by alpha-beta.
Implications for future treatment
If these results are confirmed in future studies, they may have an impact on the direction of Alzheimer’s disease drug development.
Rather than focusing solely on removing protein clumps, researchers may target the interaction between alpha-beta and microtubules. Another potential strategy would be to increase the ability of cells to remove αβ before it accumulates within neurons.
Julien believes this discovery will help connect many previously disconnected observations from Alzheimer’s disease research.
“This idea helps us understand many results that previously seemed unrelated,” Julien says. “This gives us a clearer picture of what’s going wrong within the neurons and where new treatments can begin.”
