The structure of an Amyloid Precursor Protein/talin complex indicates a mechanical basis of Alzheimer’s Disease
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Misprocessing of Amyloid Precursor Protein (APP) is one of the major causes of Alzheimer’s disease. APP is a transmembrane protein comprising a large extracellular region, a single transmembrane helix and a short cytoplasmic tail containing an NPxY motif (normally referred to as the YENPTY motif). Talin is a synaptic scaffold protein that connects the cytoskeletal machinery to the plasma membrane via binding to one of two highly conserved NPxY motifs in the cytoplasmic tail of integrin transmembrane receptors. Here we report the crystal structure of an APP/talin complex identifying a new way to couple the cytoskeletal machinery to synaptic sites via APP. Structural modelling reveals that APP forms an extracellular meshwork that mechanically couples the cytoskeletal meshworks of both the pre-, and post-synaptic compartments. In this context, we propose APP processing as a mechanical signalling pathway with similarities to Notch signalling, whereby the cleavage sites in APP represent mechanical sensors, with varying accessibility to cleavage by secretases. During synaptogenesis in healthy neurons, the APP/talin linkage would provide an exquisite mechanical coupling between synapses, with tightly controlled APP processing providing instructions to maintain this synchrony. Furthermore, APP directly coupling to the binary switches in talin indicates a role for APP in mechanical memory storage as postulated by the MeshCODE theory. The implication that APP is a regulator of mechanical signalling leads to a new hypothesis for Alzheimer’s disease, where mis-regulation of APP dynamics results in loss of mechanical integrity of the synapse, corruption and loss of mechanical binary data, and excessive generation of the toxic plaque-forming Aβ42 peptide. In support of this model, we show that talin1 depletion has a dramatic effect on APP processing in cells. Much needs to be done to experimentally validate this idea, but we present here a novel theory of Alzheimer’s Disease with a role for APP in the mechanically coded binary information storage in the synapse, which identifies a potential novel therapeutic strategy for treating Alzheimer’s Disease.
Graphical Abstract
Graphical Abstract Legend:Amyloid Precursor Protein (APP) forms an extracellular meshwork that provides a coupling between the mechanical signalling machinery of the pre- and post-synaptic neurons.
A) APP binds to talin indicating that APP will experience mechanical forces which leads us to propose that APP processing is a Notch-like signalling pathway that maintains mechanical homeostasis at the synapse. B) The crystal structure of APP bound to talin F2F3. C) APP is part of the adhesion complex that attaches talin to the membrane. D) The loss of adhesion integrity in the synapse, or other factors that lead to misprocessing of APP will perturb this coupling and contribute to Alzheimer’s Disease. See also Movie 1 .
Summary
Here we present six novel hypotheses for the role of Amyloid Precursor Protein (APP) in healthy neuronal activity and its misprocessing and memory loss in Alzheimer’s Disease (AD). These hypotheses are based on our experimental evidence of i) a direct interaction between talin and APP, ii) structural modelling of APP to scale, iii) cellular evidence of talin’s role in APP processing and iv) talin’s role in mechanical memory.
Hypothesis 1: APP forms an extracellular meshwork that mechanically couples the two sides of the synapse.
Hypothesis 2: APP processing is a mechanical signalling pathway that synchronises the synapse to ensure mechanical homeostasis.
Hypothesis 3: A mechanical basis of AD - altered mechanical cues lead to misprocessing of APP which leads to the devastating consequences of AD.
Hypothesis 4: Loss of memory is a result of corruption of the binary coding within the synapse.
Hypothesis 5: The spread of AD is due to the collapse of mechanical homeostasis that propagates through the networks.
Hypothesis 6: It might be possible to repurpose drugs that help stabilise Focal Adhesions to slow down the spread of AD
Rigorous experimental validation and refinement of these hypotheses is required next to validate these ideas in neurons and in patients. However, we believe this study identifies a previously unexplored area for APP research and a novel strategy for the development of therapeutic approaches that could revolutionise the treatment of AD.
