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Protecting the brain against dementia following traumatic injury

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A team of scientists have utilised lab-grown human brain structures known as organoids to offer insights into why traumatic brain injuries (TBI) quadruple the risk of developing dementia, and increase chances of developing neurodegenerative diseases such as ALS.

For the study, published in Cell Stem Cell, USC scientists used human patient-derived stem cells to grow rudimentary brain structures known as organoids in the lab. They then injured these organoids with high-intensity ultrasound waves.

The injured organoids showed some of the same features seen in TBI patients, including nerve cell death and pathological changes in tau proteins, as well as in a protein called TDP-43.

The scientists found that the pathological changes in TDP-43 were more prevalent in organoids derived from patients with ALS or frontotemporal dementia, making their nerve cells more susceptible to dysfunction and death following injury.

This suggests that TBI might increase the risk of developing these diseases even more for patients with a genetic predisposition. The worst injuries were sustained by nerve cells that share information, called excitatory neurons, located in the deep layers of the organoids.

In their search for ways to protect these neurons against the effects of TBI, the scientists identified a gene called KCNJ2, which contains instructions for making channels that selectively allow potassium to pass through the cell membrane, helping to enable muscle contraction and relaxation. Inhibiting this gene had a protective effect on organoids derived from patients with and without ALS, as well as on mice, following a TBI.

“Targeting KCNJ2 may reduce the death of nerve cells after TBI,” said Justin Ichida, who is the John Douglas French Alzheimer’s Foundation Associate Professor of Stem Cell Biology and Regenerative Medicine at USC, and a principal investigator at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC.

“This could have potential as either a post-injury treatment or as a prophylactic for athletes and others at high risk for TBI.”

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