A newly published study in Royal Society Open Biology provide new insight into the potential mechanical underpinnings of Alzheimer’s disease. Researchers have identified a previously unknown interaction between two proteins in the brain—amyloid precursor protein and talin—that may be fundamental to memory formation and maintenance. Their findings suggest that disruptions in this interaction could contribute to the progression of Alzheimer’s disease by impairing the brain’s ability to maintain synaptic stability, ultimately leading to cognitive decline.
Alzheimer’s disease is a progressive neurodegenerative disorder that primarily affects memory, thinking, and behavior. It is the most common cause of dementia, accounting for 60 to 80 percent of cases worldwide. The disease is characterized by the accumulation of amyloid plaques and tau tangles in the brain, which contribute to the breakdown of neural connections and the loss of cognitive function. Despite extensive research, the precise mechanisms driving Alzheimer’s disease remain poorly understood, and effective treatments remain elusive.
Previous studies have focused heavily on the toxic buildup of amyloid plaques, but this approach has yet to yield successful treatments. Researchers sought to explore an alternative explanation—whether mechanical forces within the brain play a role in disease progression
“The research in our lab is focused on how the cells in our body can sense and respond to mechanical forces. We work on the protein, talin, each of which contain tiny force-dependent binary switches that turn on and off different cellular functions, acting as a mechano-sensitive signalling hub,” said study authors Ben Goult of the University of Liverpool and Charles Ellis of the University of Southampton.
“We recently discovered a complex meshwork of these talin proteins within the scaffold protein networks that organise the synapses (neuronal connections) in our brain. As these binary switches are built into the scaffolding of every synapse in our brain, it led me to propose the MeshCODE theory. Building upon this work, we then focussed on understanding how talin and its switches control the brain, its activity and any potential dysfunction is this network that leads to disease.”
“Consequently, we recently discovered that one of the proteins that talin attaches to is the amyloid precursor protein (APP),” the researchers explained. “APP itself is known for its central role in the devastating Alzheimer’s disease, where it has been suggested that incorrect processing of the APP protein can lead to the formation of amyloid plaques seen in the brains of Alzheimer’s disease patients. This discovery led us to study precisely how talin and APP are connected, leading to a radical new view of Alzheimer’s disease.”
“In our work, we suggest that the APP-talin interaction is vital for the maintenance of healthy synaptic connections, where APP misprocessing leads to mechanical dyshomeostasis (via talin) at the synapse. We postulate that this mechanical impairment leads to the synaptic dysfunction seen in Alzheimer’s disease.”
The researchers utilized a combination of structural biology techniques, biochemical assays, and cellular experiments to explore the relationship between these two proteins and how their interaction might contribute to memory formation and maintenance.
One of the key methodologies involved X-ray crystallography and nuclear magnetic resonance spectroscopy, which allowed the researchers to determine the molecular structure of the interaction between APP and talin. They focused on a specific region within the intracellular portion of APP, known as the NPxY motif, which is known to bind to adhesion-related proteins. By mapping the binding sites of these two proteins, the researchers were able to confirm that talin directly interacts with APP, forming a mechanical link that connects the cytoskeleton to the extracellular environment at synapses.
“We were surprised that despite the billions of dollars of funding for Alzheimer’s research, there was very little literature on the full-length molecule or what it looked like,” Goult and Ellis told PsyPost. “When we modeled the APP protein in full, it was immediately obvious that APP might be (a) part of a mechanical linkage in cells and (b) might connect to the mechanosensitive machinery on both sides of the synapse. When APP is considered to be part of the force-sensitive machinery of the brain, it immediately indicates a novel role for APP in healthy brain function.”
The study also involved experiments in cultured cells to analyze the functional impact of this interaction. Using gene silencing techniques, the researchers selectively removed talin from cells and observed how this affected the processing of APP. Their findings revealed that when talin was absent, the processing of APP was altered, leading to an increase in the production of amyloidogenic fragments. These fragments are known to contribute to the formation of amyloid plaques, which are a hallmark of Alzheimer’s disease. This suggests that a loss of mechanical stability at synapses may lead to the misprocessing of APP, potentially triggering the early stages of neurodegeneration.
Furthermore, the study provided evidence that APP may function as a mechanosensor, helping neurons maintain synaptic integrity by responding to mechanical forces. In a healthy brain, this interaction likely plays a crucial role in stabilizing synapses and ensuring efficient communication between neurons. However, in Alzheimer’s disease, disruptions in this mechanical signaling pathway could weaken synaptic connections, leading to memory loss and cognitive decline. The researchers proposed that the misprocessing of APP, caused by altered mechanical forces, might be one of the driving factors behind synaptic degeneration.
One of the most exciting implications of the study is the potential for new therapeutic approaches. The researchers suggested that drugs known to stabilize focal adhesions—protein complexes that anchor cells to their surroundings—could be repurposed to restore mechanical stability at synapses. Although this idea remains theoretical, it opens the possibility of developing treatments that target the mechanical aspects of Alzheimer’s disease rather than focusing solely on amyloid plaque accumulation.
“In our work, we present a novel interaction between a key Alzheimer’s-linked protein, APP, and a mechanically sensitive synaptic scaffolding protein, talin,” Goult and Ellis explained. “From this, we suggest the APP-talin interaction is central in a pathway that leads to synaptic dysfunction, which is central to the development of Alzheimer’s disease. We end our work with six testable hypotheses, the most notable of which speculates on a potential repurposing of currently available cancer drugs, suggesting a possible treatment route to restore mechanical integrity at synapses and prevent symptomatic presentation.”
The researchers plan to investigate whether APP forms an extracellular meshwork that mechanically couples the two sides of the synapse, ensuring stability in healthy neuronal communication. They also hope to explore whether the processing of APP functions as a mechanical signaling pathway that helps maintain synaptic homeostasis and whether disruptions to this process contribute to the progression of Alzheimer’s disease.
Another key focus will be determining if altered mechanical cues lead to the misprocessing of APP, ultimately triggering synaptic degeneration and memory loss. Additionally, they aim to test whether the spread of Alzheimer’s disease results from a breakdown in mechanical stability that propagates through neural networks. Finally, the researchers are interested in whether existing drugs that stabilize focal adhesions could be repurposed to restore synaptic integrity and slow disease progression. These investigations could lead to a deeper understanding of Alzheimer’s disease and open new avenues for potential treatments.
“We hope to continue to work on the six testable hypotheses we present, with the focus on finding a novel approach to slow the progression and speed up the diagnosis of Alzheimer’s disease,” the researchers said. “We are developing mechanobiology approaches to exert forces onto these proteins, to hopefully prove that force is playing a central role in APP processing. We are currently working with clinicians to test whether cancer drugs that stabilize talin complexes in cells in culture alter APP processing in neurons to potentially slow down the spread of Alzheimer’s disease.”
The study, “The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s disease,” was authored by Charles Ellis†, Natasha L. Ward†, Matthew Rice†, Neil J. Ball, Pauline Walle, Chloé Najdek, Devrim Kilinc, Jean-Charles Lambert, Julien Chapuis, and Benjamin T. Goult.
