Recent studies conducted over the past few years have added to an increasing body of evidence that even mild forms of traumatic brain injury, most commonly referred to as concussions, may lead to long-term, irreparable damage. Even more recent research headed by an interdisciplinary team of scientists at the University of Pennsylvania (UPenn) has focused on mathematical modeling to gain a clearer understanding of the tiny mechanisms behind concussions. The researchers’ ultimate goal is to gain more knowledge that might be used to better protect people from the long-term consequences of mild traumatic brain injury.
UPenn Researches Investigate Brain Protein
The team’s recent findings, published in the Biophysical Journal, allow a closer look at the mechanical properties of a critical brain protein called tau. Tau has become a recurring theme among many levels of brain injury analysis. High levels of tau have been discovered in brain tissue via post-mortem examinations of deceased athletes with a history of multiple concussions. These analyses, along with new, preliminary tests aimed at detecting the presence of tau in living subjects, have linked the protein directly to chronic traumatic encephalopathy (CTE). As more research is conducted, tau is being discovered in many different stages of injury and is being analyzed further as the common link between concussions and the indication for long-term cognitive and psychological deficits.
In the UPenn study, researchers isolated tau and its role in the elasticity of axons, the long, tendril-like part of brain cells across which signals are transmitted. Looking more closely at tau has helped to explain the apparent contradiction this elasticity presents. If axons are normally flexible and elastic by nature, then why do they break so easily under the strain of a traumatic brain injury (concussion)?
According to the researchers, Tau’s own elastic properties explain why rapid impacts cause permanent damage to the structures within axons – when applying the same amount of force more slowly causes them to safely expand and contract without shearing. This understanding has now been applied to make computer models of the brain more realistic and may potentially be applied toward the theoretical study of tau-related diseases, such as Alzheimer’s.
Experiment Stretches Axons in an Attempt to Pinpoint the Shearing Point Where Cell Damage Occurs
The study was led by a trio of veteran researchers – Vivek Shenoy, professor of materials science and engineering in the School of Engineering and Applied Science and Hossein Ahmadzadeh, a member of Shenoy’s lab, and Douglas Smith, professor of neurosurgery in UPenn’s Perelman School of Medicine and director of the UPenn Center for Brain Injury and Repair. Shenoy said:
“One of the main things you see in the brains of patients who have died because of a TBI is swellings along the axons. Inside axons are microtubules, which act like tracks for transporting molecular cargo along the axon. When they break, there’s an interruption in the flow of this cargo and it starts to accumulate, which is why you get these swellings.”
In his earlier work, Smith had focused on the mechanical properties of axons as a whole. By patterning axons in culture in parallel tracts, Smith and his colleagues successfully stretched the axons at different forces and speeds while measuring precisely how they responded. Smith explained:
“What we saw is that with slow loading rates, axons can stretch up to at least 100 percent with no signs of damage, but at faster rates, axons start displaying the same swellings you see in the TBI patients. This process occurs even with relatively short stretch at fast rates. So the rate at which stretch is applied is the important component, such as occurs during rapid movement of the brain and stretching of axons due to head impact from a fall, assault or automobile crash.”
However, researchers encountered their main obstacle when this observation failed to explain why microtubules, the stiffest part of the axon, were the parts that were breaking. To answer the question, the team looked even deeper into their structure.
Tau’s Secret lies within its Bond to Microtubules – the Bundles of “Straws” Inside Axons
Microtubules are closely packed together inside axons, comparable to a bundle of straws or thin hollow tubes. The individual straws are bound together by the protein tau. Previous biophysical modelers had accounted for the geometry and elastic properties of the axon during a stretching injury based on Smith’s work – but did not have good data for representing tau’s role in the overall behavior of the system as it is subjected to variable stress loads over different time durations. Shenoy added:
“You need to know the elastic properties of tau because when you load the microtubules with stress, you load the tau as well. How these two parts distribute the stress between them is going to have major impact on the system as a whole.”
Shenoy and his colleagues had a general idea about tau’s elastic properties but they did not have reliable figures until a 2011 experiment by a Swiss and German research team physically stretched out lengths of tau by “plucking” it with the tip of an atomic force microscope. According to Shenoy:
“This experiment demonstrated that tau is viscoelastic. Like Silly Putty, when you add stress to it slowly, it stretches a lot. But if you add stress to it rapidly, like in an impact, it breaks.”
This behavior occurs since the strands of tau protein are coiled up and bonded to themselves in different places. Essentially, those bonds can come undone when pulled very slowly, lengthening the strand without breaking it. Shenoy added:
“The damage in traumatic brain injury occurs when the microtubules stretch but the tau doesn’t, as they can’t stretch as far. If you’re in a situation where the tau doesn’t stretch, such as what happens in fast strain rates, then all the strain will transfer to the microtubules and cause them to break.”
New, Accurate Modeling will provide for Better Focus on Long-Term Damage in Brain Tissue
With a comprehensive model of the tau-microtubule system, the researchers gained the ability to break down the outcome of rapid stress loading to equations using only a handful of variables. This new mathematical understanding allows the researchers to produce a phase diagram that shows the dividing line between strain rates that leave permanent damage versus safe and reversible loading and unloading of stress.
In the long term, clearly understanding the parameters that lead to irreversible damage could lead to a much better understanding of brain injuries and similar diseases – and ultimately to new preventive measures. It may even be possible to design drugs that alter microtubule stability and elasticity of axons in traumatic brain injury. Additionally, Smith’s research group has demonstrated that treatment with the microtubule-stabilizing drug taxol reduced the extent of axon swellings and degeneration after stretch injury.
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