The creation of a ‘mini brain’ is set to give greater insight into the link between concussion and Alzheimer’s disease.
The ‘traumatic brain injury (TBI) on a chip’ being developed will make it possible to track the effects of a concussive force on a functioning cluster of brain cells.
And research by Purdue University has revealed that changes in these cells can take place within a matter of hours.
“We’re basically creating a miniature brain that we can hit and then study,” said lead researcher Dr Riyi Shi.
“We know there’s a link between TBI and Alzheimer’s; that’s well established in clinical observation. But teasing out the basic essential pathway is not easy.
“With the TBI on a chip, we’re able to test a lot of hypotheses that would be very difficult to do in living animals.”
In a recent study, a research team led by Dr Shi subjected functioning clusters of cultured neurons from embryonic mice to three blows of 200 g-force, each approximating the higher end of what a football player receives in a single hit.
The trauma leads to an immediate surge in production of acrolein — a molecule associated with oxidative stress and neurodegenerative disease — and a rise in misfolded clumps of the protein amyloid beta 42 (AB42), which is found in masses called plaques in the brains of people with Alzheimer’s disease. Additional experiments traced the links between impact, acrolein and AB42.
The device can also be used to test possible therapeutics, including drugs known to reduce acrolein levels.
In the current study, Dr Shi’s team used the device to show that the drug hydralazine, a known acrolein scavenger that is approved by the US Food and Drug Administration for lowering blood pressure, reduces the amount of acrolein and levels of misfolded AB42 produced in the cluster of neurons after a hit.
Dr Shi, who has a long history of studying neurodegenerative disease, acrolein and hydralazine, said the TBI on a chip enabled a finding he’s sought over two decades of study.
“Now that we know what’s happening, is there something we can do about it? And the answer is yes,” said Dr Shi.
“Acrolein is time-dependent; the longer it’s there, the more AB42 aggregation it will cause. Here we show that if we lower acrolein with this drug, we can lower inflammation and AB42 aggregation.”
The device, custom-fabricated at the Purdue Center for Paralysis Research, uses a pendulum to deliver a specific g-force to a small chamber housing a cluster of a quarter million neurons supported by a bed of nutrients.
A microelectronic array embedded in the chamber measures the electrical activity of the neurons, which will sustain functional firing patterns for several weeks, while a clear viewing port allows microscopic observation of the neurons.
Researchers remove the cluster of neurons from the chamber at intervals to take specific biochemical measurements.
“There’s several unique things that we do here, but one of the biggest is that you can hit this chip without damaging it, so you can give an impact to a live model and continue to study it,” Dr Shi said.
“Thanks to this device, people should know that when you get a concussion, you don’t have ten years before you will see damage.
“The clock starts ticking immediately, and if we want to do something about it, we need to act quickly.”
Within the first 24 hours after a hit, results show elevated levels of acrolein in the neuron clusters and a 350 per cent increase in production of misfolded AB42.
Dr Shi said acrolein deforms normal AB42 by binding to sections of the protein that contribute to structural stability.
Indeed, when the team conducted a simple experiment by combining large amounts of acrolein with normal purified AB42 suspended in fluid, they found elevated levels of misfolded AB42. The properly folded protein is sufficiently fragile that even subjecting normal purified AB42 in fluid (without acrolein) to an impact was enough to provoke misfolding.
“This amyloid beta pathology started within hours, maybe immediately. That’s never been heard of,” Dr Shi said.
“It’s like attacking the weight-bearing stud in a house wall. If you break that stud, of course the house is going to fall down.”
