A new path of cell death in Alzheimer’s disease and vascular dementia has been discovered by researchers. Ferroptosis, a type of cell death caused by an accumulation of iron in cells, destroys microglia cells, a type of cell involved in the brain’s immune response, in Alzheimer’s and vascular dementia, a study led by scientists at Oregon Health & Science University has found.
The researchers examined post-mortem human brain tissue from dementia patients. Senior author Stephen Back, M.D., Ph.D., said this is a major finding.
Back has long studied myelin, the protective insulation-like sheath surrounding nerve fibers in the brain, as well as delays in myelin formation in premature neonates. The new research extends this line of inquiry by identifying a cascading form of neurodegeneration caused by myelin deterioration.
The discovery was made utilizing a novel technique developed by the study’s main author, a postdoctoral researcher in Back’s laboratory, Philip Adeniyi, Ph.D.
Ferroptosis
Microglia degenerates in the white matter of the brain of patients with Alzheimer’s and vascular dementia, according to the researchers.
As part of the body’s immune system, microglia, which are resident cells in the brain, are typically involved in removing cellular waste. Microglia invade injured myelin to clean the debris.
The current study discovered that the procedure of removing iron-rich myelin destroys microglia — a type of cell death known as ferroptosis.
Given the intense scientific focus on the underlying cause of dementia in older adults, Back found it amazing that researchers hadn’t made the connection to ferroptosis until now.
“We’ve missed a major form of cell death in Alzheimer’s disease and vascular dementia. We hadn’t been giving much attention to microglia as vulnerable cells, and white matter injury in the brain has received relatively little attention,”
Back said.
Dying in the Line of Duty
According to Back, co-author Kiera Degener-O’Brien, M.D., discovered the degeneration of microglia in tissue samples first.
Adeniyi then devised a unique immunofluorescence approach to show that iron toxicity was inducing microglial degeneration in the brain. This was most likely because myelin fragments are high in iron, said Back.
Immune cells were effectively dying in the line of duty.
“Everyone knows that microglia are activated to mediate inflammation. But no one knew that they were dying in such large numbers. It’s just amazing that we missed this until now,”
Back said.
Cognitive Loss Cascade
The study found that the cascading effect of degenerating microglia appears to be a mechanism in progressive cognitive loss in Alzheimer’s disease and vascular dementia.
Credit: Annals of Neurology (2023). DOI: 10.1002/ana.26770
Back anticipates that pharmaceutical companies will exploit this new discovery to produce drugs aimed at lowering microglial degeneration in the brain.
“That’s where the field will go next,” he said. “A discovery like ours will stimulate a lot of excitement in the pharmaceutical industry to develop therapeutically important compounds.”
Back believes the underlying cause of the decline cycle is likely related to repeated episodes of low blood flow and oxygen delivery to the brain over time caused by 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,”
Back said.
Reference:
- Adeniyi, P.A., Gong, X., MacGregor, E., Degener-O’Brien, K., McClendon, E., Garcia, M., Romero, O., Russell, J., Srivastava, T., Miller, J., Keene, C.D. and Back, S.A. (2023). Ferroptosis of microglia in aging human white matter injury. Ann Neurol. Accepted Author Manuscript
Top Image credit: Annals of Neurology (2023). DOI: 10.1002/ana.26770
Last Updated on November 11, 2023