A Bold Theory Could Push Alzheimer’s Disease Research In A New Direction

Alzheimer’s disease is one of the major health challenges facing humankind today. Recent years have seen the development of the most promising drug treatments we’ve ever seen, as well as trials of innovative therapies and tests. But debates around what actually causes the disease continue to rage in the background. Into this fray steps a new theory, in which an intricate dance between two proteins could, the authors suggest, indicate a “mechanical basis” of Alzheimer’s disease.

The study has just been posted as a preprint, and so has not yet undergone external peer review. In their paper, the international team of authors detail the experimental process that led them to develop a six-pronged hypothesis for how a protein called talin, through its interactions with a key Alzheimer’s protein called amyloid precursor protein (APP), could be a vital mediator in the development of the disease – and, crucially, how it might be possible to target this system with drugs.

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

Goult’s history with the talin protein goes back several years. In 2021, he put forward a novel view for how memories may be stored in the brain called the MeshCODE theory. Taking advantage of a talin molecule’s ability to switch between two stable shapes, the theory suggests that memories could be encoded physically like a mechanical computer uses binary switches, with one talin shape acting as the “0” and the other as the “1”. 

   

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

“The key steps on the way were […] showing experimentally that talin does bind APP [and] when we modelled APP to 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 see immediately what is going on.”

  

With these results in hand, Goult quickly contacted Dr Julien Chapuis at the Institut Pasteur de Lille, France. Chapuis’ team had been systematically assessing different proteins’ effects on APP, but had excluded talin from their published research as it had not met their cut-off criteria.

“But when you look at the data, talin has just about the biggest effect on APP processing out of all proteins!” Goult told IFLScience.

“So combined with our work on talin as a memory molecule and the MeshCODE, I realised this was all starting to fit together, then I started to write this new paper. As it all started to fit together it was really amazing, and seeing the genetic data and the biochemical data all fit together made the last couple of months of writing this 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 across which nerve impulses must pass. Correct processing of APP is vital to maintain the synchronicity of the synapse, but this can go wrong, ultimately leading to Alzheimer’s through corruption of the binary code we talked about earlier – the MeshCODE of talin “1s” and “0s”. As this collapse spreads throughout brain networks, so Alzheimer’s disease spreads through the brain. 

“This study provides a new idea for what APP might be doing in healthy neuronal functioning. And that when 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 incorrect processing of APP – that are seen in the brains of sufferers.

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

To be totally clear, this is all still in the realm of the theoretical. But Goult and colleagues suggest that “rigorous experimental validation and refinement of these hypotheses” should be the next step – something they’re already working on in the lab, with hopes for animal experiments 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. 

Focal adhesions (FAs) are large globs 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 some drugs that are known to stabilize FAs – they’re often used in cancer treatment. Could these also have the same effect on APP in the brain, restabilizing the APP mechanical mesh and preventing the breakdown that leads to Alzheimer’s?  

It’s a tantalizing thought, and something Goult and colleagues are very keen to explore further. 

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

“It’s [really] cool working on the individual proteins and how they work, look and interact as it can lead to completely new ideas that scale through all the levels of explanation from complexes to synapse to neurons to a whole brain,” Goult told IFLScience.

“With a bit of luck this new data and the hypotheses that arise from it can accelerate new ways to treat this disease.”

The preprint, which is yet to undergo external peer review, is available at bioRxiv

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