Summary: Researchers have created a “traumatic brain injury (TBI) on a chip” to investigate how concussions might trigger processes linked to Alzheimer’s disease.
Using clusters of neurons grown from embryonic mouse cortex, the team exposed these miniature, functioning neural networks to g-forces comparable to those experienced in high-impact sports. The model revealed an immediate spike in acrolein, a toxic byproduct associated with oxidative stress and neurodegeneration, and a substantial rise in misfolded amyloid‑beta 42 (Aβ42), the protein closely tied to Alzheimer’s pathology.
The device also served as a platform to test potential interventions: the antihypertensive drug hydralazine, known to scavenge acrolein, reduced both acrolein and misfolded Aβ42 levels in the neuronal clusters following impact.
Key Facts:
- The TBI-on-a-chip indicates that within 24 hours of an impact there can be a 350% increase in misfolded Aβ42, linking the immediate biochemical consequences of concussion to mechanisms implicated in Alzheimer’s disease.
- The platform integrates a microelectronic array to record neuronal electrical activity, enabling functional assessment that is difficult to obtain in living animals.
- Hydralazine, an FDA-approved medication for lowering blood pressure, acted as an acrolein scavenger in this model and lowered both acrolein and misfolded Aβ42 after simulated concussive blows.
Source: Purdue University
How quickly does a head blow begin processes linked to Alzheimer’s disease?
A new experimental tool that lets researchers hit and then monitor a living cluster of brain cells suggests those pathological processes begin within hours. The traumatic brain injury (TBI) on a chip, developed at Purdue University, recreates clinically relevant concussive forces in a highly controlled, observable environment—letting scientists follow early events that can unfold into decades-long neurodegeneration.
“We’re basically creating a miniature brain that we can hit and then study,” said Riyi Shi, lead investigator and the Mari Hulman George Endowed Professor of Applied Neuroscience in Purdue’s College of Veterinary Medicine. He noted that while clinical studies have long associated TBI with increased Alzheimer’s risk, identifying the direct mechanistic pathway has been challenging. The TBI-on-a-chip allows systematic testing of hypotheses that are difficult to pursue in whole-animal models.
In a study published in Lab on a Chip, Shi’s group delivered three impacts of roughly 200 g each to cultured neuronal networks—forces similar to the high end of single hits recorded in football. These hits provoked a rapid rise in acrolein and a concurrent increase in aggregated, misfolded Aβ42—an early hallmark of Alzheimer’s pathology. Further tests traced how mechanical force, acrolein production, and Aβ42 aggregation are linked.
The team also demonstrated the model’s utility for screening therapeutics. They showed that hydralazine, which is FDA-approved for controlling blood pressure and acts as an acrolein scavenger, reduced acrolein buildup and decreased levels of misfolded Aβ42 after impact in the neuronal clusters.
Shi, who has studied neurodegeneration, acrolein, and hydralazine for many years, said the device enabled a long-sought observation: the immediate onset of harmful biochemical events after concussion and the possibility of intervening early. “Acrolein is time‑dependent; the longer it persists, the more Aβ42 aggregation it promotes,” he explained. “If we reduce acrolein with a drug like hydralazine, we can lessen inflammation and Aβ42 aggregation.”
The custom device, built at the Purdue Center for Paralysis Research, uses a pendulum mechanism to deliver controlled g-forces to a small chamber containing roughly a quarter‑million neurons supported by nutrient medium. An embedded microelectrode array records electrical activity from the network, which remains functionally active for weeks, while a clear viewing port permits microscopic observation. Researchers periodically remove the neuronal cluster for biochemical assays.
One key advantage of this system is that the chip itself withstands impact, allowing repeated study of the same living network after a blow. Over decades of development—starting in Shi’s graduate work—the apparatus has been refined to permit combined mechanical, biochemical, and electrophysiological measurements. A 2022 paper using this device first documented the post-impact acrolein surge; the current study extends that work by showing how acrolein promotes early Aβ42 misfolding and functional decline.
The findings emphasize urgency: concussion-related damage begins immediately, not years later. Within 24 hours after impact, neuron clusters showed elevated acrolein and a roughly 350% increase in misfolded Aβ42 production. In complementary experiments, applying acrolein directly to purified Aβ42 increased its misfolding, and even physical impact on purified Aβ42 in fluid could induce structural changes—evidence that both primary mechanical forces and secondary chemical injury contribute to early amyloid pathology.
“This amyloid beta pathology started within hours, maybe immediately,” Shi said. He compared the effect to compromising a house’s structural stud: once that support is damaged, the structure is more likely to fail.
Coauthors on the study include Edmond A. Rogers (first author), Timothy Beauclair, Jhon Martinez, Shatha J. Mufti, David Kim, Siyuan Sun, Rachel L. Stingel, Nikita Krishnan, Jennifer Crodian, and Alexandra M. Dieterly. The research received support from the state of Indiana, the National Institutes of Health, and Plexon Inc.
Looking ahead, Shi plans to add capabilities to the chip that would measure the tiny forces cells experience during an impact and perform biochemical assays—such as acrolein measurement—without removing cells from the chamber, enabling even more detailed, time-resolved studies.
About this Alzheimer’s disease and concussion research news
Author: Mary Martialay
Source: Purdue University
Contact: Mary Martialay – Purdue University
Image: The image is credited to Neuroscience News
Original Research: Closed access. “The contribution of initial concussive forces and resulting acrolein surge to β-amyloid accumulation and functional alterations in neuronal networks using a TBI-on-a-chip model” by Riyi Shi et al. Lab on a Chip
Abstract
The contribution of initial concussive forces and resulting acrolein surge to β-amyloid accumulation and functional alterations in neuronal networks using a TBI-on-a-chip model
Trauma‑related Alzheimer’s disease is increasingly recognized as a severe outcome of traumatic brain injury (TBI), imposing serious social and economic costs. Progress toward effective treatments has been limited by gaps in understanding the early mechanisms that link head trauma to later neurodegeneration.
A clinically relevant in vitro model that mirrors in vivo dynamics with high spatial and temporal resolution is essential to disentangle these pathways. Using a TBI-on-a-chip system with murine cortical networks, the authors show correlated increases in oxidative stress (acrolein), inflammation (TNF‑α), and Aβ42 aggregation, accompanied by reduced neuronal network electrical activity after concussive impact.
The results validate the TBI-on-a-chip as a complementary tool to in vivo studies for exploring trauma-induced Alzheimer’s mechanisms. The experiments demonstrate that acrolein acts as a diffusive secondary-injury factor that is sufficient to promote inflammation and Aβ42 aggregation—two central contributors to Alzheimer’s pathogenesis. Cell‑free preparations further confirm that both mechanical force and acrolein can independently and synergistically induce aggregation of purified Aβ42.
Beyond biochemical and morphological assessment, simultaneous monitoring of neuronal activity confirms that acrolein contributes not only to molecular pathology but also to functional network deficits. Overall, the TBI-on-a-chip quantitatively links force-dependent increases in oxidative stress, inflammation, protein aggregation, and impaired network activity, offering a powerful platform for mechanistic studies and therapeutic testing in post‑TBI Alzheimer’s research.
This model is expected to provide key insights into pathological mechanisms and help guide the development of diagnostics and treatments that could benefit people affected by TBI.