Queensland Brain Institute (QBI) researchers have identified that a newly discovered form of cell death may help explain why memory declines with age.
Researchers from QBI’s Walker lab have found that ferroptosis, a type of cell death linked to iron and oxidative stress, plays an unexpected role in the healthy brain by influencing how many newborn neurons survive in the hippocampus, a region critical for learning and memory.
According to Associate Professor Tara Walker and Dr Alison Carlisle, this discovery opens a new pathway for future drug development aimed at improving neurogenesis and supporting memory in ageing.
“Ferroptosis has been identified in almost every neurological disorder where cells are dying, including Alzheimer’s disease, Parkinson’s disease and stroke,” Associate Professor Walker said.
“But we wanted to know whether it also had a role in normal brain function.”
The QBI team focused on adult neurogenesis, the process where neural stem cells in the hippocampus divide, mature and can become new neurons.
These newborn neurons help support learning and memory, but the process slows with age.
Dr Alison Carlisle said the study found ferroptosis was one way that neural stem cells were lost in the ageing brain.
“In ageing, neurogenesis is decreased and along with that you have decreased cognition,” she said.
“We found that hippocampal neural precursor cells were especially vulnerable to ferroptosis-related stress.
“When compounds that block ferroptosis were given to aged mice, the animals produced more new neurons and performed better in spatial learning and memory tasks.”
The discovery builds on earlier work from Associate Professor Walker’s lab showing selenium supplements could increase neuron production and improve cognition in elderly mice.
Selenium is important because it helps regulate GPX4, a protein that protects cells from ferroptosis.
“GPX4 is a selenoprotein, so selenium levels help mediate the expression of that protein,” Associate Professor Walker said.
“That gave us a clue. We knew selenium increased neurogenesis and cognition, but we didn’t know the mechanism.
“Ferroptosis helped explain how selenium might be protecting these cells from dying.”
Dr Carlisle said the findings suggest ferroptosis may not only be a destructive process in disease, but also part of the brain’s normal system for maintaining balance.
“This is the first report of a physiological role for ferroptosis in maintaining that balance,” she said.
“It’s all about balance - not simply to make the brain produce as many new neurons as possible.
“When the brain is already performing well, you don’t necessarily want to increase neurogenesis.
“But when there’s a deficit, such as in ageing, stroke or neurodegenerative disease, this pathway may give us a way to help restore function.”
The paper was published in Cell Stem Cell.
