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Why Brain Cells Change Their Inner Skeleton in Alzheimer’s

Reference: Venkatramani, A. & Panda, D. (2019). Regulation of neuronal microtubule dynamics by tau: Implications for tauopathies. International Journal of Biological Macromolecules, 133, 473–483.

Guest post by Agnes Adler

To function, our brains must be flexible. As you’re reading this article, your brain is busy forming new connections and adapting its structure. To facilitate this learning process, our nerve cells undergo continuous changes. They not only create new connections, but also retract old ones to ensure our focus isn’t constantly hijacked by irrelevant memories. But how do these changes happen? The secret players are microtubules – long and hollow tubes that run inside nerve cells.

Researchers have recently found that microtubules – and particularly their malfunctioning – are also connected to one of the most prevalent neurodegenerative disorders that causes memory loss and eventually leads to death: Alzheimer’s disease. One of the key mysteries scientists have been focusing on, in fact, is why brain cells undergo significant changes in their internal structure – their “cellular skeleton” – during Alzheimer’s progression. This alteration is believed to be linked to one crucial stabilizer of the microtubules, which forms plaques in the brains of individuals affected by this devastating disease.

To understand the challenges of Alzheimer’s research and potential targets for intervention, let us explore the underlying biological foundation of the disease.

The cell has a dynamic skeleton

Just like the human body relies on a skeletal system composed of bones, cells have their own structural framework, called the cellular skeleton. This intricate network supports transportation and movement within the cell, allowing it to function properly. Microtubules are crucial components for this process.

Unlike our body’s static skeleton, however, microtubules constantly form and disassemble, thanks to their peculiar structure. Just like LEGO pieces, they are composed of subunits, which can assemble and disassemble in desired lengths and shapes.

The cell has a skeleton just like the body has one. An important component of this cellular skeleton are microtubules.

Although microtubules are present in every cell of our body, they are especially highly concentrated in nerve cells, and predominantly in their extensions of such cells, which look like tentacles. Here, microtubules are needed for stability and transport of important nutrients, working like railway tracks on which a train runs: their sheer presence makes the nerve cell stable and allows helpers to move along the tubes and carry cargo with them from one side of the cell to another.

 A nerve cell is not a tentacle monster, but their appearances are similar.

The extensions send and receive messages from one nerve cell to another, allowing us to think, move, feel, and do all those other things that make life worth living.

Why is the cell skeleton dynamic?

Microtubules assemble and disassemble in a constant, well-controlled manner. They build new structures where needed, while retracting from regions that no longer require their support. Moreover, they ensure that nutrition and other essential materials are brought to sides that have to be maintained and used, while excluding unused or unimportant regions. This delicate dance ensures our brains remain adaptable throughout our lives. But microtubules can’t do it alone. They are regulated by valuable partners, such as the protein tau.

What is tau?

Tau is a protein found in high concentrations in nerve cells, where it stabilizes microtubules. You can compare the tau function to a clamp that holds together the microtubule which otherwise falls apart into its subparts.

The protein tau holds together the microtubule, just like a hair clamp does with hair.

Microtubule dynamics and memory loss

Researchers noticed in 1986 that Alzheimer’s disease disrupts microtubules’ dynamic behavior, but could tau play a role? The answer seems to be “yes”. Although the exact reason is still unknown and researchers argue over the cause-and-effect order of the disease, a wrong biochemical modification of tau is observed in Alzheimer’s disease. The differently-modified tau protein cannot bind to the microtubules, causing microtubules’ instability and hence less structure and less transport in the nerve cell. This process is comparable to the human skeleton in which calcium serves as a small, but essential component to build a bone.

But there’s more to the story with Alzheimer’s. Improperly modified tau proteins bind to each other and form clumps or plaques typically observed in the brains of individuals with Alzheimer’s disease. These clumps, referred to as “tangles” due to their resemblance to long strands clustering together, create a build-up of difficult-to-remove waste material, placing an excessive burden on nerve cells. You can compare this process to trash building up in a city: the consequences of waste accumulation can include lung diseases, polluted rivers, and a clogged infrastructure. In the human brain, “trash” tangles and microtubule instability lead to the death of the nerve cell. If a nerve cell dies, it cannot communicate with neighboring nerve cells, so a stored memory is lost. People who experience this process many times over will forget important information like where they put their keys, where they parked their bike, and eventually, where they live.

In Alzheimer’s, the protein tau is improperly modified and builds tangles instead of stabilizing microtubules.

Conclusion

After decades of dedicated research into Alzheimer’s disease, scientists are finally beginning to see the puzzle pieces come together, bringing us closer to a potential cure. While the search for drugs and therapies to clear the plaques associated with the disease has so far been challenging, there is renewed hope on the horizon. With our newfound understanding of microtubule stability, the possibility of combining plaque-clearing medications with microtubule-stabilizing agents emerges as an exciting possibility for a cure. Let us remain optimistic and hope for a world where Alzheimer’s becomes a distant memory.

Agnes is a PhD student in biomolecular Nuclear Magnetic Resonance Spectroscopy at Utrecht University in the Netherlands who is about to defend her thesis. Her research focuses on understanding microtubule interactions with their associated proteins.

Original artwork in this post is by Agnes!

Connect with her on LinkedIn.

Additional References:

1.         Sakakibara, A., Ando, R., Sapir, T. & Tanaka, T. (2013). Microtubule dynamics in neuronal morphogenesis. Open Biol. 3, 130061.

2.         McKenney, R. J. (2022). Alzheimer’s disease-implicated protein tau puts the squeeze on microtubules. Nat. Chem. Biol. 18, 1172–1173.

3.         Naseri, N. N., Wang, H., Guo, J., Sharma, M. & Luo, W. (2019). The complexity of tau in Alzheimer’s disease. Neurosci. Lett. 705, 183–194.