Unpacking Ferroptosis: What Does a Build-up of Iron Do to the Brain?

New research has discovered a new biological process involved in Alzheimer's disease. This process is called ferroptosis. This may open up new treatment options for Alzheimer's disease. More research is needed to understand the role of ferroptosis.¹

Ferroptosis is a way for our cells to self-destruct using iron. People with Alzheimer's disease are more prone to ferroptosis in the brain. This is because of:¹

• Abnormal iron regulation
• White matter damage
• Low blood flow

In Alzheimer's disease, ferroptosis leads to:¹

• Cell death
• Inflammation
• Decline in mental processes (cognitive decline)

What is ferroptosis?

Ferroptosis is a type of "programmed cell death" that depends on iron. Programmed cell death (PCD) is a process our cells use to self-destruct. It removes damaged cells or cells that are no longer needed. PCD is controlled by many proteins and chemicals in the body.²

The result of ferroptosis is damage to fatty acids. Fatty acids make up our cell membranes. They can be attacked by certain free radicals (called reactive oxygen species). This results in oxidation of fatty acids, or "lipid peroxidation." This, in turn, destroys the structure of the cell membrane and leads to cell death.^1,3

Iron plays a key role in how our cells make reactive oxygen species. Our cells need a balance between different forms of iron. They also need a balance between import and export of iron. An imbalance can make cells more prone to ferroptosis.^1,3

Antioxidants in our cells help work against ferroptosis. An enzyme called GPX4 undoes lipid peroxidation. GPX4 needs a chemical called glutathione in order to work. Reducing glutathione levels makes cells more prone to ferroptosis.^1,3

How is ferroptosis linked to Alzheimer's disease?

When PCD does not work well, it can lead to disease. For example, cancer cells have ways to avoid PCD. On the other hand, too much PCD can lead to neurodegenerative diseases such as Alzheimer's disease. These are diseases in which the nervous system becomes damaged over time.²

Aging is a risk factor for Alzheimer's disease and iron buildup in the brain. Those with Alzheimer's disease have abnormal iron regulation. Brain cells are also rich in the fatty acids that are most prone to lipid peroxidation. Combined, this makes brain cells in Alzheimer's disease more vulnerable to ferroptosis. Studies have shown that those with Alzheimer's disease have:^1,3

1. Increased iron in the brain
2. Higher levels of proteins that import iron into brain cells
3. Lower levels of proteins that export iron out of brain cells
4. Lower levels of glutathione and GPX4 activity
5. More fatty acids that are prone to lipid peroxidation

This is why experts believe ferroptosis plays a role in Alzheimer's disease. It leads to:^1,3

• Inflammation
• Cell death
• Cognitive issues

The hallmarks of Alzheimer's disease are beta-amyloid plaques and clusters of Tau proteins. It is not clear how ferroptosis is linked to these processes. They may all be part of a harmful cycle.^1,3

How does ferroptosis affect white matter?

White matter is the network of nerve fibers in the brain. It allows information exchange around the brain to happen. It is called "white" because the nerve fibers are protected by myelin. This gives the tissues a white color.^4,5

White matter needs good blood flow to stay healthy. Low blood flow causes damage to white matter. This can cause lesions, which show up as bright spots on brain scans. Damage to white matter during aging is common in Alzheimer's disease. This makes the brain more prone to ferroptosis.⁴

How does ferroptosis affect cognitive health and decline?

Ferroptosis plays a role in cognitive health. Research has linked it to vascular cognitive impairment (VCI). VCI refers to memory and thinking issues caused by impaired blood flow to white matter. Symptoms range from mild cognitive problems to dementia. VCI can occur alone or as part of Alzheimer's disease.⁶

Low blood flow in the brain is called cerebral hypoperfusion (CCH). CCH lowers your antioxidant mechanisms and boosts iron buildup. This makes the brain more prone to ferroptosis. It leads to lipid peroxidation, which causes cell death and cognitive decline.^6,7

How can addressing ferroptosis treat Alzheimer's disease?

Blocking ferroptosis may help treat Alzheimer's disease. Certain drugs may work in different ways to reduce iron-dependent lipid peroxidation. Some examples include drugs that:^1,8

• Mop up reactive oxygen species (ferrostatin-1, liproxstatin-1, vitamin E)
• Increase your body’s antioxidant activities (baicalein, melatonin)
• Block enzymes that cause lipid peroxidation (zileuton)
• Bind iron to make it less reactive (curcumin, deferoxamine)

Where does the research go from here?

We have only recently discovered ferroptosis. We need to learn more about how it is linked to other processes in Alzheimer's disease. We also need to understand its role in the different stages of Alzheimer's disease.¹

Current research is looking to see if blocking ferroptosis can treat Alzheimer's disease. In separate clinical studies, vitamin E and deferoxamine slow cognitive decline. Meanwhile, ferrostatin-1 and liproxstatin-1 improve memory in mouse models of Alzheimer's disease.^1,8

We do not have enough information to know how well these drugs work. A single ferroptosis drug may not be enough to treat Alzheimer's disease. We may need to combine ferroptosis blockers with other drugs that treat Alzheimer's disease.^1,8