"Mini-brain" Sheds Light on the Link Between Concussions and Alzheimer's
How much time elapses between a blow to the head and the start of damage associated with Alzheimer’s disease?
A device that makes it possible to track the effects of concussive force on a functioning cluster of brain cells suggests the answer is in hours. The “traumatic brain injury (TBI) on a chip” being developed at Purdue University opens a window into a cause and effect that announces itself with the passage of decades but is exceedingly difficult to trace back to its origins.
In a study recently published in Lab on a Chip, a research team led by 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, Shi’s team used the device to show that the drug hydralazine, a known acrolein scavenger that is approved by the U.S. 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. 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.
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.
Shi began working on the device in graduate school, incorporating over the course of several decades features that make it possible to study the aftereffects of an initial blow. A 2022 paper in Nature Scientific Reports used the device to show the surge in acrolein that occurs after a hit, and Shi said the most recent findings hint at the power of the model.
Within the first 24 hours after a hit, results show elevated levels of acrolein in the neuron clusters and a 350% increase in production of misfolded AB42. She 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.
Shi was joined in the research by Purdue colleagues Edmond A. Rogers, first author, and co-authors Timothy Beauclair, Jhon Martinez, Shatha J. Mufti, David Kim, Siyuan Sun, Rachel L. Stingel, Nikita Krishnan and Jennifer Crodian, senior research associate at Purdue’s Center for Paralysis Research, as well as Alexandra M. Dieterly of Charles River Laboratory. The study was supported by the state of Indiana, the National Institutes of Health and Plexon Inc.
Moving forward, Shi said, he may be able to incorporate multiple additional features, which would allow the measurements of minute forces that cells experience during the blow, and biochemical testing — like checking levels of acrolein — without removing cells from the chamber. Industry partners interested in further developing or commercializing Shi’s innovation should contact Joseph Kasper of the Purdue Innovates Office of Technology Commercialization at firstname.lastname@example.org.