Ferroptosis, which is caused by a buildup of iron in cells, appears to be a major mechanism of white matter injury in Alzheimer’s disease and vascular dementia, according to a new study.
White matter degenerating microglia are a novel therapeutic target to potentially reduce the impact of white matter injury and myelin loss on the progression of cognitive impairment. Image credit: Miroslaw Miras.
“This is a major finding,” said Professor Stephen Back, a neuroscientist at Oregon Health & Science University.
“We’ve long studied myelin, the insulation-like protective sheath covering nerve fibers in the brain, including delays in forming myelin in premature infants.”
“Our new research extends that line of work by uncovering a cascading form of neurodegeneration triggered by deterioration of myelin.”
Professor Back and colleagues discovered that microglia degenerates in the white matter of the brain of patients with Alzheimer’s and vascular dementia.
Microglia are resident cells in the brain normally involved in clearing cellular debris as part of the body’s immune system. When myelin is damaged, microglia swarm in to clear the debris.
In the study, the researchers found that microglia themselves are destroyed by the act of clearing iron-rich myelin — a form of cell death known as ferroptosis.
“We’ve missed a major form of cell death in Alzheimer’s disease and vascular dementia,” Professor Back said.
“We hadn’t been giving much attention to microglia as vulnerable cells, and white matter injury in the brain has received relatively little attention.”
The authors initially discovered the degeneration of microglia in tissue samples.
Subsequently, they developed a novel immunofluorescence technique to determine that iron toxicity was causing microglial degeneration in the brain.
This was likely a result of the fact that the fragments of myelin are themselves rich in iron. In effect, the immune cells were dying in the line of duty.
“Everyone knows that microglia are activated to mediate inflammation,” Professor Back said.
“But no one knew that they were dying in such large numbers. It’s just amazing that we missed this until now.”
The scientists found that the cascading effect of degenerating microglia appears to be a mechanism in advancing cognitive decline in Alzheimer’s disease and vascular dementia.
They expect pharmaceutical companies will use this new finding to develop compounds focused on reducing microglial degeneration in the brain.
“That’s where the field will go next,” Professor Back said.
“A discovery like ours will stimulate a lot of excitement in the pharmaceutical industry to develop therapeutically important compounds.”
“The underlying cause initiating the cycle of decline likely relates to repeated episodes of low blood flow and oxygen delivery to the brain over time due to acute stroke or chronic conditions such as hypertension and diabetes.”
“Dementia is a process that goes on for years and years. We have to tackle this from the early days to have an impact so that it doesn’t spin out of control.”
A paper on the findings was published in the journal Annals of Neurology.
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Philip A. Adeniyi et al. Ferroptosis of microglia in aging human white matter injury. Annals of Neurology, published online August 21, 2023; doi: 10.1002/ana.26770
