A bold theory could push Alzheimer’s research in a new direction

Alzheimer’s disease is one of the greatest health challenges facing humanity today. In recent years we have developed the most promising drug treatments we have ever seen, as well as trials of innovative therapies and tests. But debates about what actually causes the disease continue to rage in the background. A new theory is playing a role in this battle, in which an intricate dance between two proteins, the authors suggest, could point to a “mechanical basis” of Alzheimer’s disease.

The research has just been published as a preprint and has therefore not yet undergone external peer review. In their paper, the international team of authors describe the experimental process that led them to develop a six-part hypothesis about how a protein called talin, through its interactions with a key Alzheimer’s protein called amyloid precursor protein (APP), could play a crucial role play in the development of the disease. mediator in the development of the disease – and, crucially, how it might be possible to combat this system with drugs.

We spoke with senior author Dr. Ben Goult, Professor of Mechanistic Cell Biology at the University of Liverpool, about the new work.

Goult’s history with talin protein goes back several years. In 2021, he presented a new view on how memories can be stored in the brain, the MeshCODE theory. By exploiting a talin molecule’s ability to switch between two stable forms, the theory suggests that memories could be physically encoded the way a mechanical computer uses binary switches, with one talin form acting as the “0” and the other as the “1”.

Since then, a series of experimental findings have led Goult and team to believe that talin is not only involved in writing memory in the brain, but could also play a role in its loss during the development of Alzheimer’s disease.

“The most important steps along the way were […] experimentally demonstrate that talin binds APP [and] when we modeled APP at scale,” Goult told IFLScience. “If you look at this video we made, it’s all drawn to scale using full-length proteins, and you can immediately see what’s going on.”

With these results in hand, Goult quickly contacted Dr. Julien Chapuis of the Institut Pasteur de Lille, France. Chapuis’ team had systematically assessed the effects of various proteins on APP, but had excluded talin from their published research because it did not meet their cutoff criteria.

“But if you look at the data, talin has about the largest effect on APP processing of any protein!” Goult told IFLScience.

“So combined with our work on talin as a memory molecule and the MeshCODE, I realized this was all starting to fit together, and that’s when I started writing this new paper. When it all started to come together it was really amazing, and seeing the genetic data and the biochemical data all fit together made the last few months of writing incredibly exciting.”

The authors suggest that APP proteins could exist in a mesh that mechanically connects the two sides of a synapse, the gap between two neurons over which nerve impulses must pass. Correct processing of APP is essential to maintain synapse synchrony, but this can go wrong and ultimately lead to Alzheimer’s disease due to corruption of the binary code we talked about earlier – the MeshCODE of talin “1s” and “ 0s”. As this collapse spreads through brain networks, Alzheimer’s disease also spreads through the brain.

“This study provides a new idea of ​​what APP might do to healthy neuronal functioning. And that if this goes wrong, you get defects in mechanical homeostasis, and this can lead to problems,” Goult told IFLScience.

The theory also fits with our current, evolving understanding of Alzheimer’s pathology and the role of the plaques of misfolded amyloid-β protein – caused by improper APP processing – seen in patients’ brains.

“But I think it also identifies some possible new ways to treat or at least diagnose Alzheimer’s disease earlier,” Goult added.

To be clear, this is all still within the realm of theory. But Goult and colleagues suggest that “rigorous experimental validation and refinement of these hypotheses” should be the next step – something they are already working on in the lab, with the hope of animal testing in the near future.

This also ties in with the crucial sixth part of the hypothesis: that it might be possible to repurpose existing drugs to help slow the spread of Alzheimer’s disease.

Focal adhesions (FAs) are large blobs of protein that connect machinery inside a cell to the outside environment. Previous genetic data suggest a link between the stability of FAs and the stability of APP at the synapse. But we already have a number of drugs known to stabilize FAs; they are often used in the treatment of cancer. Could these also have the same effect on APP in the brain, re-stabilizing APP’s mechanical network and preventing the breakdown that leads to Alzheimer’s?

It’s a tempting thought, and something that Goult and colleagues are eager to explore further.

Goult’s journey with Talin is already paved with some surprises, and we can now add this bold new theory to that list.

“Are [really] cool to work on the individual proteins and how they work, look and interact, because it can lead to completely new ideas that span all levels of explanation, from complexes to synapses to neurons to an entire brain,” shared Goult to IFLScience.

“With any luck, these new data and the hypotheses arising from them could accelerate new ways to treat this disease.”

The preprint, which has yet to undergo external peer review, is available on bioRxiv.

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