Abstract
Traumatic brain injuries are a leading cause of morbidity and mortality worldwide. With almost 50% of traumatic brain injuries being related to axonal damage, understanding the nature of cellular level impairment is crucial. Experimental observations have so far led to the formulation of conflicting theories regarding the cellular primary injury mechanism. Disruption of the axolemma, or alternatively cytoskeletal damage has been suggested mainly as injury trigger. However, mechanoporation thresholds of generic membranes seem not to overlap with the axonal injury deformation range and microtubules appear too stiff and too weakly connected to undergo mechanical breaking. Here, we aim to shed a light on the mechanism of primary axonal injury, bridging finite element and molecular dynamics simulations. Despite the necessary level of approximation, our models can accurately describe the mechanical behavior of the unmyelinated axon and its membrane. More importantly, they give access to quantities that would be inaccessible with an experimental approach. We show that in a typical injury scenario, the axonal cortex sustains deformations large enough to entail pore formation in the adjoining lipid bilayer. The observed axonal deformation of 10–12% agree well with the thresholds proposed in the literature for axonal injury and, above all, allow us to provide quantitative evidences that do not exclude pore formation in the membrane as a result of trauma. Our findings bring to an increased knowledge of axonal injury mechanism that will have positive implications for the prevention and treatment of brain injuries.
Highlights
Traumatic brain injury (TBI) is defined as “an alteration in brain function, or other evidence of brain pathology, caused by an external force” [1]
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]
A previously published and validated axon finite element (FE) model was used (Figure 1A), which is a 8 μm long representative volume (RV) of an axon consisting of three main compartments: a microtubule (MT) bundle, the neurofilament (NF) network and, the axolemma-cortex complex wrapping the entire structure [26]
Summary
Traumatic brain injury (TBI) is defined as “an alteration in brain function, or other evidence of brain pathology, caused by an external force” [1]. In 2013, ∼2.8 million TBI-related emergency department visits, hospitalization, and deaths occurred in the United States [2]. Diffuse axonal injury (DAI), a multifocal damage to white matter axons, is the most common consequence of TBIs of all severities including mild TBIs or concussions [4]. Invisible to conventional brain imaging, DAI can only be histologically diagnosed and its hallmark is the presence of axonal swellings or retraction balls observable under microscopic examination [5].
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