New discovery could offer significant answers on Alzheimer’s disease

A new study from the University of Liverpool represents a significant step forward in scientists’ understanding of Alzheimer’s disease.

Researchers have shed new light on how mechanical signalling in the brain is disrupted and could lead to the condition which accounts for 60-80% of dementia cases worldwide.

The team of investigators, led by Professor Ben Goult at the University of Liverpool, have examined the role of two proteins found in the brain and suggest the stability of their relationship to one another is crucial for memory formation and maintenance. Disruptions in this mechanical signalling pathway could lead to the disease. This is the first time this connection has been identified and could pave the way for therapeutic interventions.

The newly published paper proposes that Amyloid Precursor Protein (APP), known for its role in the formation of the amyloid plaques in the brain, that are a characteristic feature in Alzheimer’s disease (AD), directly interacts with talin, a synaptic scaffold protein. For the first time, it’s suggested the talin-APP interaction is crucial for the mechanical integrity of synapses in the brain and that the misprocessing of APP observed in Alzheimer’s, disrupts mechanical signalling pathways, leading to synaptic degeneration and memory loss, thereby contributing to the progression of AD. The paper further shows that if talin is removed from cells in culture then the processing of APP is dramatically altered.

Professor Ben Goult, University of Liverpool said: “Alzheimer’s disease is a cruel neurodegenerative disorder characterised by memory loss and cognitive decline. It is a global health challenge, yet little is known about the underlying mechanisms that lead to the disease. However, this paper gives us a new piece of the puzzle and significantly advances research.

“Our paper outlines that APP is fundamental for the mechanical coupling of synapses in the brain and how the processing of APP is part of a mechanical signalling pathway that maintains synaptic integrity. However, misprocessing of APP, due to altered mechanical cues, disrupts this pathway, leading to the synaptic degeneration observed in Alzheimer’s and could explain the memory loss associated. What’s most exciting is our paper highlights the intriguing possibility that repurposing currently available cancer drugs that stabilize focal adhesions might represent a way to restore mechanical integrity at synapses. Whilst currently this is only a theoretical prediction, our current research is focussed on testing whether this represents a novel approach to slow the progression of Alzheimer’s.

“Further research is needed to test the theories that emerge from these new findings. However, this marks a significant moment in better understanding this disease and could move us closer to early diagnosis and treatment.”

The paper, ‘The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s disease‘, was published in the Royal Society Open Biology Journal (DOI: https://doi.org/10.1098/rsob.240185)