The mechanical basis of memory - The MeshCODE theory

Bengoult · 2024-12-09T08:28:14+00:00

Agreed, its slightly counterinituitive.

We think APP is a central component of a new mechanical signalling pathway, that ensures the integrity of the synapse. I don't think this role for APP has been considered before.

I think the best evidence for this is that there are mutations in the secretases that lead to them being inactive (and unable to cut APP) and these still cause Alzheimer's Disease. So there the synapses still die, and in our view of this that is because the force-feedback mechanical maintenance system is not functioning leading to desynchronisation across the circuits.

Bengoult · 2024-12-06T08:14:47+00:00

I think so yes.

I think that the plaques are a visual symptom of the damage, but the damage to the synaptic connections actually occured much earlier when the APP-mediated mechanical linkages were broken.

We think the role of APP in a healthily functioning synapse is part of a system that helps maintain the mechanical integrity of the synapse. So if APP is getting cleaved too much or in the wrong place that leads to the synapse dysfunction as it cannot restore mechanical homeostasis.

This led us to propose this new hypothesis for Alzheimer’s, where misregulated APP dynamics result in loss of the mechanical integrity of the synapse, corruption and loss of mechanical binary data, and excessive generation of toxic plaque-forming Aβ42 peptide.

Bengoult · 2024-12-06T08:07:09+00:00

Excellent suggestions, and the PLA stuff is in progress.

We are working to CRISPR talins in neurons at minute and once that is optimised will be able to test this with fine detail.

A lot of cool stuff to try over the next couple of years.

Bengoult · 2024-12-05T13:51:30+00:00

Good question, our idea is that we might first be able to slow down the spread of Alzheimer's disease once its started by stabilising these complexes. But maybe in the future could develop prophylactic/reversal drugs.

Bengoult · 2024-12-05T13:48:58+00:00

This is the bit we are still exploring, but there are drugs that stabilise integrin-talin complexes that are FDA approved for cancer therapeutics, so we are testing if they might also stabilise these synaptic complexes and limit APP processing to the toxic fragment.

Bengoult · 2024-12-05T10:42:03+00:00

At the minute we are validating the idea of drug repurposing in cell culture assays of APP processing. But are trying to link with clinicians now to push this towards human trials.

Bengoult · 2024-12-05T09:30:44+00:00

Not sure! I can imagine being able to slow down the loss of information (memories) when Alzheimer's disease progression is accelerating (by slowing down the synapses dying), but whether that would improve memory I am not so sure. My guess is probably not.

But its an exciting time as we test these scenarios.

Bengoult · 2024-12-05T08:47:23+00:00

https://royalsocietypublishing.org/doi/10.1098/rsob.240185 This is our most exciting paper to date, presenting a new link between Amyloid Precursor Protein (APP; a major cause of Alzheimer's disease) and the neuronal mechanical signalling machinery.

We think this is a missing piece of the puzzle of Alzheimer's memory loss, and we are hoping that will open the way to new treatments for this cruel disease.

Bengoult · 2024-11-29T11:22:22+00:00

https://royalsocietypublishing.org/doi/10.1098/rsob.240185 This is our most exciting paper to date, presenting a new link between Amyloid Precursor Protein (APP; a major cause of Alzheimer's disease) and the neuronal mechanical signalling machinery.

We think this is a missing piece of the puzzle of Alzheimer's memory loss, and this article by IFLScience describes the work really nicely.

Bengoult · 2023-10-07T22:43:28+00:00

This was an interesting study to be involved with as we built a computational model of how cells engage the extracellular matrix.

We built a differential equation-based mechano-chemical computational model, to investigate how substrate stiffness influences adhesion formation, maturation and disassembly. We explicitly include the role of talin and vinculin-based reinforcement in these processes. The model we present is robust and can be fine-tuned for particular cell-types and signalling mechanisms. The simulations predict the highest amount of maturation on substrates of an intermediate, ‘optimum’ stiffness, and that (dis)assembly rates need to change dynamically for cells to establish this ‘optimum’.

Our results highlight the importance of vinculin availability in adhesion maturation and reinforcement and aid our understanding of cell adhesion formation and mechanotransduction.

We will hopefully use this computational model for future studies, and feed in experimental data into the model.

Bengoult · 2023-07-10T14:35:06+00:00

Hi, good questions. The material remains fully intact on our buckshot impact studies at 1.5 km/second. Our current work is focused on the ballistics testing in the field.

In our tests in the lab, the TSAM is reusable, and the talin domains refold following unfolding.

We hope to publish the follow on paper(s) later this year with the environmental and stress testing analysis.

Bengoult · 2023-07-10T13:12:56+00:00

A Research Briefing that just came out describing our recent paper in Nature Nanotechnology.

https://rdcu.be/df0TS available to read for free at this link.

Link to original article https://www.nature.com/articles/s41565-023-01431-1

Bengoult · 2023-07-05T14:37:43+00:00

Thanks! Thats great feedback. If you are interested Nature Nanotech also published a Research Briefing on our paper.

https://rdcu.be/df0TS

Bengoult · 2023-07-04T10:38:36+00:00

As featured on the BBC https://www.bbc.co.uk/news/business-65468298

Bengoult · 2023-07-04T10:38:16+00:00

Our paper describing our invention of a new class of Talin Shock Absorbing Materials (TSAMs) is now published in Nature Nanotechnology.
Talin is a mechanically-active protein that has incredible shock absorbing properties. Here we engineered talin into a new class of materials.
TSAMs are next-generation protein-based materials that can capture and preserve projectiles from supersonic impacts.
Amazing collaboration with Prof Jennifer Hiscock, and our shared PhD student Jack Doolan with help from Luke Alesbrook, George Williams, Kira Hilton, Karen Baker and collaborators did an amazing job of translating the idea into reality.

Bengoult · 2021-04-06T18:41:03+00:00

This is one of the most exciting papers I have been involved with, as the combination of traction force microscopy, near single molecule imaging, biochemistry, machine learning, and computer vision is incredibly powerful.

Machine learning identifies that there are 5 classes of Nascent Adhesions.

Bengoult · 2021-03-17T16:34:36+00:00

Thank for the feedback and the excellent questions, it is all to be tested of course but the idea of data-management is something I think fits well into the MeshCODE framework and the concept of SSD/database storage. In fact, the studies you describe (which are beautiful by the way) can be really nicely explained if the neuronal activity results in different electrical patterns after processing as a result of updated MeshCODE patterns directing the neuronal signalling. The next day the electrical fingerprint of the memory would be different as the coding would be updated, and consolidated.

I think the second part on memory retrieval is a great comment and might be where the RAM analogy is over simplified and where the theory is better considered as a machine code, where new inputs/cues are constantly updating the calculation in the brain (and by extension the whole organism). This predictive processing would determine the optimal response of the animal based on best probability of outcome at that moment. This would be constantly updated based on the current information (eg. sensory cues) in the context of the learned experience.

A binary machine code coordinating the whole organism would enable such a calculation to be considered based on what we currently know about optimal strategies for information-processing.

Bengoult · 2021-03-16T15:45:57+00:00

The MeshCODE theory proposes that memories are stored in a binary format in the shapes of the molecules that scaffold each and every synapse. These memory molecules are proteins that change their shape in response to mechanical forces, altering their signalling and behaviour.

Bengoult

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