Suffering a traumatic brain injury (TBI) can increase your risk of developing dementia fourfold and also raise the likelihood of developing neurodegenerative diseases like ALS. USC scientists have conducted a new study published in Cell Stem Cell, using lab-grown human brain structures called organoids to gain insight into why this happens and how to reduce the risk.
The study conducted by former postdoc Jesse Lai and PhD student Joshua Berlind from the USC Stem Cell laboratory of Justin Ichida used human patient-derived stem cells to cultivate rudimentary brain structures called organoids. These organoids were then exposed to high-intensity ultrasound waves to simulate injury.
As a result, the injured organoids exhibited similar characteristics to those observed in patients with traumatic brain injury (TBI), such as nerve cell death and abnormal changes in tau proteins and TDP-43.
It was also discovered that the changes in TDP-43 were related to the injury, providing insights into the underlying mechanisms and potential ways to reduce the risk.
Organoids from patients with ALS or frontotemporal dementia showed a higher presence of TBI, making their nerve cells more vulnerable to dysfunction and death after injury. This indicates that TBI could further increase the risk of developing these diseases for patients with a genetic predisposition. The most severe damage was observed in excitatory neurons located in the deep layers of the organoids.
To protect these neurons from TBI effects, researchers found a gene called KCNJ2, which contains instructions for making selective channels.
By inhibiting the KCNJ2 gene, it was found that the passage of potassium through the cell membrane was reduced. This helped to protect organoids derived from both ALS patients and non-ALS patients, as well as mice, after experiencing a traumatic brain injury (TBI).
According to Ichida, who is the John Douglas French Alzheimer’s Foundation Associate Professor of Stem Cell Biology and Regenerative Medicine at USC, targeting the KCNJ2 gene could potentially decrease the death of nerve cells following a TBI. This could be beneficial as a treatment option after an injury or as a preventative measure.phylactic for athletes and others at high risk for TBI.”
About the authors and the study
Co-corresponding author Ichida is also a co-founder of AcuraStem and Modulo Bio, a member of the Scientific Advisory Board (SAB) at Spinogenix and Vesalius Therapeutics, and works in the Research and Early Development group at BioMarin Pharmaceutical. Co-corresponding author Lai and co-author Violeta Yu were both employees of Amgen during the study, and currently work at Dewpoint Therapeutics. The named companies were not involved in this research project.
The first author, Berlind, is a PhD student in the Ichida Lab. Additionally,Co-authors include Gabriella Fricklas, Cecilia Lie, Jean-Paul Urenda, Kelsey Lam, Naomi Sta Maria, Russell Jacobs, and Zhen Zhao from USC. 50% of the work received federal funding from the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (grant F31NS117075), NINDS (grant R01 1R01NS097850-01), and the Department of Defense (grant 12907280). The project also had private funding from an Amgen postdoctoral fellowship, the New York Stem Cell Foundation, the Tau Consortium, the Harrington Discovery Institute, the Alzheimer’s Drug Discovery Foundation, and the Association for Fronto.temporal Dementia and the John Douglas French Alzheimer’s Foundation.
