A new study published in Royal Society Open Biology has provided new information on the potential mechanical mechanisms behind Alzheimer’s disease. The study found that disruption of the similar amino acid precursor protein (APAP)-talin interaction of AP photon ALK and ALK BAP II may interfere with the formation and maintenance of memory. The most severe type of neurodegeneration, Alzheimer’s disease, affects memory, thinking and behaviour. It accounts for 60 to 80 percent of dementia cases worldwide.
The disease is caused by the formation of amyloid plaques and tau tangles in the brain, which disrupt neural connections and lead to cognitive decline. Despite extensive research, the mechanisms behind Alzheimer’s disease are not fully understood, and treatments remain problematic.
The toxic accumulation of amyloid plaques has been the subject of numerous studies throughout history, yet no successful treatments have been discovered. To address this, the researchers investigated the possibility of brain mechanical forces contributing to the development of the disease.
The study, conducted by study authors Ben Gault and Charles Ellis, focused on analyzing how mechanical forces affect cell function in the body. They studied talin, a protein that contains tiny force-dependent binary switches that act as a mechanical hub for signaling.
The discovery of talin proteins inside neuron scaffolding networks led me to propose the Meshcode theory.
The researchers found that talin binds to amyloid precursor protein (APP), a PhD research topic.
Mechanical dyshomeostasis of synapses through talin is a result of mechanical impairment caused by APP-talin interactions, which are essential for preserving healthy synaptic connections. According to our hypothesis, this mechanical impairment is thought to be the cause of synaptic dysfunction associated with Alzheimer’s disease.
Using structural biology techniques, biochemical assays and cellular experiments, the researchers determined that the two proteins are interdependent and may play a role in the maintenance and formation of memory.
Using X-ray crystallography and nuclear magnetic resonance spectroscopy, the researchers were able to identify the molecular structure of the interaction between talin and APP. They specifically targeted the NPxY motif located in the intracellular portion of talin, which binds to adhesion-related proteins. By mapping the binding sites of these proteins, they confirmed that talin and APP interact directly, bind to synapses (symmetral contacts) and form a mechanical connection to membranes.
The fact that there was so little literature on the full-length molecule or its appearance was unexpected, according to Gault and Ellis, who spoke to PsyPost.
In addition, the researchers conducted experiments on cultured cells to investigate the functional impact of the interaction. They used gene silencing techniques to remove talin from cells and observed how it was removed from solution, and when talin was absent, the researchers observed that the response to processing APP was altered, resulting in increased production of amyloidogenic fragments. This suggests that loss of mechanical stability in synapses may have caused the early stages of neurodegeneration.
Furthermore, the study proved that APP can act as a mechanosensor, assisting neurons in preserving synaptic integrity by responding to mechanical forces. This interaction is likely the primary driver of synaptic stabilization and communication in a healthy brain.
However, in cases of Alzheimer’s disease, disruption of this pathway can weaken synaptic connections, leading to memory loss and cognitive decline. The researchers suggested that incorrect processing of APP, due to altered mechanical forces, may be one of the causes of synaptic degeneration.
The study findings may provide new therapies that stabilize proteins known to stabilize cell adhesions. The researchers proposed that these drugs could be used to restore the mechanical stability of synapses, allowing for further treatment of the mechanical aspects of Alzheimer’s disease rather than just the accumulation of amyloid plaques.
Gault and Ellis demonstrated a new interaction between APP, an important Alzheimer’s-linked protein, and talin, a mechanically sensitive synaptic scaffolding protein. They suggest that APP plays a key role in synaptic dysfunction, a key factor in the development of Alzheimer’s disease.
They conclude by proposing six testable hypotheses, one of which suggests the potential repurposing of existing cancer drugs, suggesting a treatment route to regain mechanical integrity at synapses and prevent symptomatic presentation.
The team aims to investigate whether APP forms an extracellular meshwork that connects the two sides of a synapse in a way that maintains stability in healthy neuronal communication.