The misprocessing of amyloid precursor protein (APP) is a key factor in the development of Alzheimer’s disease. APP consists of a large extracellular region, a transmembrane helix, and a short cytoplasmic tail with an NPxY motif known as the YENPTY motif. Talins are synaptic scaffold proteins that bind to the NPxY motifs, specifically in integrins, linking the cytoskeleton to the plasma membrane.
A new study from the University of Liverpool significantly advances the understanding of Alzheimer’s disease. Researchers have uncovered how mechanical signaling in the brain is disrupted, potentially contributing to the development of the condition, which accounts for 60-80% of dementia cases globally.
Researchers have identified a crucial interaction between the brain’s proteins, Amyloid Precursor Protein (APP) and talin. This relationship is essential for memory formation and maintenance. Disruptions in this mechanical signaling pathway could lead to Alzheimer’s disease (AD).
The study reveals that APP, which is vital for amyloid plaque formation in AD, interacts with talin to maintain synaptic integrity. Misprocessing of APP in Alzheimer’s disrupts these pathways, causing synaptic degeneration and memory loss. Additionally, removing talin from cells significantly alters APP processing, further supporting its role in AD progression.
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Professor Ben Goult, University of Liverpool, said: “Alzheimer’s disease is a cruel neurodegenerative disorder characterized 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 puzzle piece 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 signaling 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. While 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.”
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“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.”
Journal Reference:
- Charles Ellis, Natasha L. Ward, Matthew Rice, Neil J. Ball, Pauline Walle, Chloé Najdek, Devrim Kilinc, Jean-Charles Lambert et al. The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s disease. Open Biology. DOI: 10.1098/rsob.240185
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