Three SoCoBio-DTP students, Charles Ellis, Natasha Ward and Matthew Rice are happy to share their contribution to a publication published in Open Biology (Royal Society): “The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s disease” (https://royalsocietypublishing.org/doi/10.1098/rsob.240185). 

In this work, we identified a novel interaction between amyloid precursor protein (APP – linked to Alzheimer’s Disease causation) and the cytoskeletal scaffold protein, talin. We report the crystal structure of the APP/talin1 complex alongside biochemical data (nuclear magnetic resonance, fluorescence polarisation binding data) indicating a new mechanical linkage at the synapse (the junctions between neurons). Structural modelling suggested a potential extracellular network of APP that mechanically couples and synchronises the pre- and post-synapse via cytoskeletal interactions with talin. Finally, using primary and secondary cellular models we showed APP-talin proximity in neurons and dramatic effects on APP processing upon talin depletion. 

Together, these findings lead us to a new hypothesis of Alzheimer’s Disease, in which mis-regulated APP dynamics lead to mechanical dys-homeostasis at the synapse. We present six testable hypotheses as future directions for this research.

For a short video summary: https://youtu.be/csMs8-ZUHt4?si=HKpoJd7fMA2g-Eb1.