Alzheimer’s and Parkinson’s: iron build-up ‘stresses’ neurons and increases the risk

A veritable hidden enemy. It silently accumulates amongst the nerve cells, weighing down the neurons until they become less resilient. Then, gradually, the nerve cells become less able to cope with the body’s stresses, lose their ability to respond to damage and, ultimately, are at greater risk of degenerating. This is what is thought to occur in a biological process dubbed ‘chronoferroptosis’ by researchers, which explains how the accumulation of iron within the neurons themselves is linked to the neurodegenerative processes leading to diseases such as Alzheimer’s and Parkinson’s. Experts at the Salk Institute, led by Pam Maher (whose first name is Nawab John Dar), have defined this pathway and opened up new avenues for the prevention and treatment of these neurodegenerative processes in a highly original study published in *Cell Death Discovery*.

According to the research, the effect of intraneuronal iron accumulation appears to vary with age. In the early stages of life, practically nothing happens. But the situation changes as the years go by. Gradually, a link emerges between this accumulation and neurodegenerative diseases. They discovered that excess iron accumulated in neurons reduces cellular defences, making the cells more vulnerable to stressors and other cellular insults through a process they have termed chronoferroptosis. What would happen? Maher herself explains this to some extent in a note from the Institute: “The study reveals that cells lose resilience when iron reaches a certain level, making neurons more susceptible to stresses that damage or even kill them.” But be warned. These invisible mechanisms then have an impact on a person’s neuropsychological wellbeing. “These aspects have clinical implications,” notes Matteo Pardini, Professor of Neurology at the University of Genoa and the IRCCS AOM in the Ligurian capital – to the extent that even some patients with neurodegenerative cognitive disorders are often found to have excess iron deposits in areas critical for memory and movement.”

Let’s be clear. Iron is essential for the body’s wellbeing, as it is involved in the synthesis of haemoglobin and thus enables the normal transport of oxygen, promotes hormone production, and has a positive effect on the body’s energy production and immune defences. However, experts highlight the extent and impact of its accumulation. According to American experts, the hypothesis is that, over time, a malfunction occurs in the mechanism by which nerve cells eliminate iron. Consequently, iron enters the neurons as usual, but is not eliminated properly. However, the negative effects of this lack of ‘cleansing’ only become apparent after a very long time. This naturally raises the question: why is this the case? It is on this point that research is opening up important avenues of inquiry.

Using human nerve cells, the team at the Salk Institute has created the first progressive model of iron accumulation in neuronal cells. The problem is that the adverse effects of this lack of ‘cleansing’ only become apparent after a very long time. How can these temporal differences be explained? Using human nerve cells, the team at the Salk Institute has in fact created the first progressive model of iron accumulation in neuronal cells, going beyond the classic process of ferroptosis. The scientists compared the effects of acute (between six and eight hours) and chronic (nine days) exposure to iron. They compared the effects of acute (between six and eight hours) and chronic (nine days) exposure to iron. What they discovered was an entirely new pathway, which they have named chronoferroptosis. Ferroptosis itself, however, is already well known: it is a process of cell death linked to lipid peroxidation, similar to what is observed when a nut goes rancid. But chronoferroptosis adds a temporal dimension to ferroptosis, and whilst it does not always lead to cell death, it can alter the stress response in a way that somehow promotes degeneration. “It is precisely this dual nature of iron,” continues Pardini, “that makes any therapeutic strategy complex: the body needs it at a systemic level, and the problem seems to be a loss of regional regulation rather than an overall excess of iron.” “That is why simply ‘removing’ it is not enough: a highly selective intervention is needed, targeted at the right location and at the right time.”

In neurons exposed to iron during the acute phase, therefore, only minimal biochemical changes are observed. However, if exposure is prolonged, certain intracellular processes are altered, leading to the accumulation of harmful chemicals, a reduction in protective substances, and an increase in lipid peroxidation – and thus a risk of cell death. Not only that: when faced with stress, neurons that have only recently been exposed to iron are able to cope with the situation, but those chronically exposed cannot. And it is here that ferroptosis becomes chronoferroptosis, with consequent risks: “Entering this state of chronoferroptosis could predispose neurons to age-related cognitive decline,” reveals Dar. “So it is not the amount of iron that determines the fate of these cells, but the length of time they spend under stress.” The future aim, by understanding when the brain becomes vulnerable to iron along a hypothetical timeline, could be to intervene with treatments that counteract iron imbalances, keeping neurons resilient for longer. “But it will take time,” concludes Pardini, “not least because this research is still based on cellular models – a promising avenue to be followed with interest, but also with caution.”