Physical Biology of Axonal Damage

Abstract

Excessive physical impacts to the head have direct implications on the structural integrity at the axonal level. Increasing evidence suggests that tau, an intrinsically disordered protein that stabilizes axonal microtubules, plays a critical role in the physical biology of axonal injury. However, the precise mechanisms of axonal damage remain incompletely understood. Here we propose a biophysical model of the axon to correlate the dynamic behavior of individual tau proteins under external physical forces to the evolution of axonal damage. To propagate damage across the scales, we adopt a consistent three-step strategy: First, we characterize the axonal response to external stretches and stretch rates for varying tau crosslink bond strengths using a discrete axonal damage model. Then, for each combination of stretch rates and bond strengths, we average the axonal force-stretch response of n = 10 discrete simulations, from which we derive and calibrate a homogenized constitutive model. Finally, we embed this homogenized model into a continuum axonal damage model of [1-d]-type in which d is a scalar damage parameter that is driven by the axonal stretch and stretch rate. We demonstrate that axonal damage emerges naturally from the interplay of physical forces and biological crosslinking. Our study reveals an emergent feature of the crosslink dynamics: With increasing loading rate, the axonal failure stretch increases, but axonal damage evolves earlier in time. For a wide range of physical stretch rates, from 0.1 to 10 /s, and biological bond strengths, from 1 to 100 pN, our model predicts a relatively narrow window of critical damage stretch thresholds, from 1.01 to 1.30, which agrees well with experimental observations. Our biophysical damage model can help explain the development and progression of axonal damage across the scales and will provide useful guidelines to identify critical damage level thresholds in response to excessive physical forces.

The axonal actin-spectrin lattice acts as a tension buffering shock absorber

“…1) [22] and delineating the contributions of the different components is not trivial. It has been generally assumed that bundled microtubules are the main mechanical element in axons [23,24]. However, our results demonstrate that Factin and spetcrin play a very prominent role in axonal mechanical response.…”

“…Hence, the effects of microtubule perturbation, for instance, may be more complex than a simple change in their numbers. Microtubule bundles alone can account for softening if their cross-linkers (MAPs) exhibit binding-unbinding dynamics, but such models give a long time fluid like response [23,24] and also cannot account for the peak in the relaxation time vs strain plot. Thus, while microtubules may be making a direct contribution to the effective moduli we measure, microtubule elasticity alone cannot account for the entire set of experimental observations we report.…”

“…However, our results demonstrate that Factin and spetcrin play a very prominent role in axonal mechanical response. Furthermore, we see that axons behave as strain-softening, viscoelastic solids at long times, unlike a fluidlike state predicted by pure microtubule based models that invoke cross-link detachments [23,24]. For these reasons, and to obtain some insight into how the actin-spectrin skeleton contributes, we first consider the actin-spectrin skeleton alone and model its response to mechanical stretch.…”

Localized axolemma deformations suggest mechanoporation as axonal injury trigger

“…41–47 More recently, FE models of the axon have been proposed to shed a light on the mechanism behind axonal injury. 25,26,48–50…”

“…18,19 These studies have further motivated the development of models (both analytical and computational) having the microtubule bundle as a focus. 20–25 In our previous work, however, we have shown with a finite element model of the entire axon that, especially when including detachment of tau protein elements, deformations in the microtubules did not pass the suggested microtubule failure thresholds. 26 On the contrary, we found that, as a result of axonal stretching and of microtubules distancing, very high strain localization formed on the axonal membrane.…”