Researchers at the Salk Institute announced on June 25 that iron accumulation in neurons may play a significant role in increasing vulnerability to neurodegenerative diseases such as Alzheimer's and Parkinson's. The study, published in Cell Death Discovery on June 18, found that excess iron trapped inside nerve cells lowers their defenses over time, making them more susceptible to cellular stress through a process named chronoferroptosis.
Pam Maher, PhD, senior and co-corresponding author and research professor at Salk, said, "Resilience has become a huge topic of discussion when it comes to Alzheimer's disease and other neurodegenerative disorders, trying to make the brain more resilient in the face of stressors that contribute to neurodegeneration. Our study reveals that cells lose resilience when iron hits a certain level, making neurons more susceptible to stressors that damage or even kill them."
The researchers explained that while iron is an essential mineral for healthy bodily function—including oxygen transport and hormone production—its gradual buildup within neurons appears problematic only later in life. Nawab John Dar, PhD, co-corresponding author and postdoctoral researcher in Maher's lab, said, "So, it isn't the iron itself that is a problem with age. It is this accumulation of iron over time that is the problem." The team suspects this buildup results from failures in neuronal iron export mechanisms.
To investigate further, the Salk team developed what they describe as the first progressive model of iron accumulation using human-derived nerve cell lines. They compared acute (six-to-eight-hour) versus chronic (nine-day) exposures to excess iron. While acutely exposed neurons showed little change after exposure or additional stressors, chronically exposed neurons displayed multiple biochemical changes—including elevated lipid peroxidation—and became less able to withstand further insults.
"We think these coordinated alterations in iron-handling and antioxidant defense proteins make chronically exposed neurons vulnerable to neurodegenerative pathology," Dar said. "Entering this state of chronoferroptosis may set neurons up for age-related failure." The findings suggest ferroptosis can act not only as an immediate cell death pathway but also as a longer-term cellular stress response mechanism.
Maher concluded by noting potential future applications: "It's not something we worked on in this paper, but our lab has developed several compounds to inhibit this pathway. This could really be a promising therapeutic route for boosting neuron resilience and staving off neurodegeneration as we grow older."
