Scientists discovered a new cause of Alzheimer’s, vascular dementia

Study highlights microglia degeneration in brain caused by iron toxicity.

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A recent study set out to identify the key characteristics of this novel population of aging human microglia because it is unclear what function white matter (WM) degenerating microglia plays in myelination failure.

OHSU scientists have discovered a new avenue of cell death in Alzheimer’s and vascular dementia. They demonstrated for the first time that microglia cells, a type of cell involved in the brain’s immunological response, are destroyed in cases of Alzheimer’s and vascular dementia by a type of cell death known as ferroptosis, which is brought on by an accumulation of iron in cells.

This study used post-mortem human brain tissue of patients with dementia.

Scientists have spent a lot of time researching myelin, the protective sheath that provides insulation for the nerve fibers in the brain, and delays in myelin formation in premature infants. The new study builds on that body of work by revealing a cascading type of neurodegeneration brought on by myelin degradation.

Scientists used a novel technique developed by the study’s lead author, Philip Adeniyi, Ph.D., a postdoctoral researcher in Back’s laboratory.

They discovered that in the white matter of the brains of people with Alzheimer’s and vascular dementia, microglia degrade.

The body’s immune system employs resident brain cells called microglia to remove cellular waste. Microglia swarm in to remove the debris when myelin is injured. According to the results of a recent study, ferroptosis, a kind of cell death characterized by the removal of iron-rich myelin, causes the death of microglia.

It was amazing that the link to ferroptosis hadn’t been made earlier, given the intense scientific focus on the root cause of dementia in older people.

Stephen Back, M.D., Ph.D., a neuroscientist and professor of pediatrics at the OHSU School of Medicine, said, “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.”

“Co-author Kiera Degener-O’Brien, M.D., initially discovered the degeneration of microglia in tissue samples. Adeniyi subsequently 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. But no one knew that they were dying in such large numbers. It’s just amazing that we missed this until now.”

“The study finds that the cascading effect of degenerating microglia appears to be a mechanism in advancing cognitive decline in Alzheimer’s disease and vascular dementia. 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. 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 it doesn’t spin out of control.”

Journal Reference:

  1. Philip A. Adeniyi, Xi Gong, Ellie MacGregor et al. Ferroptosis of microglia in aging human white matter injury. Annals of Neurology. DOI: 10.1002/ana.26770
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