New Cause of Alzheimer’s and Vascular Dementia Unveiled

A new pathway of cell death in Alzheimer’s disease and vascular dementia has been found by researchers.

A new study led by researchers at Oregon Health & Science University and published online on Aug. 21 in the journal Annals of Neurology reveals for the first time that 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 cases of Alzheimer’s and vascular dementia.

The investigation was carried out by evaluating post-mortem human brain tissue from dementia sufferers.

“This is a major finding,” said senior author Stephen Back, M.D., Ph.D., a neuroscientist and professor of pediatrics in the OHSU School of Medicine.

Back has long been interested in myelin, the insulation-like protective sheath that covers nerve fibers in the brain, as well as delays in myelin formation in preterm infants. The new study expands on that work by revealing a cascade kind of neurodegeneration caused by myelin degradation. They achieved the discovery using a unique technique devised by the study’s lead author, postdoctoral researcher Philip Adeniyi, Ph.D., in Back’s laboratory.

The researchers revealed that microglia deteriorate in the white matter of Alzheimer’s and vascular dementia patients’ brains.

Microglia are brain resident cells that ordinarily clean cellular debris as part of the body’s immune system. Microglia swarm in to remove debris when myelin is injured. The current study discovered that the procedure of removing iron-rich myelin destroys microglia — a type of cell death known as ferroptosis.

Given the considerable scientific attention on the fundamental cause of dementia in older persons, Back found it incredible that researchers hadn’t identified the connection to ferroptosis before now.

“We’ve missed a major form of cell death in Alzheimer’s disease and vascular dementia,” 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.”

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. According to Back, this was most likely due to the fact that myelin fragments are high in iron.

Immune cells were, in effect, dying in the line of duty.

“Everyone knows that microglia are activated to mediate inflammation,” Back said. “But no one knew that they were dying in such large numbers. It’s just amazing that we missed this until now.”

According to Back, the study discovered that the cascading effect of degenerating microglia appears to be a mechanism in progressive cognitive loss in Alzheimer’s disease and vascular dementia. He anticipates that pharmaceutical companies will exploit this new discovery to create 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.”

He believes that the fundamental reason of the decline cycle is likely related to recurrent episodes of poor blood flow and oxygen supply to the brain caused by acute stroke or chronic diseases such as hypertension and diabetes.

“Dementia is a process that goes on for years and years,” Back said. “We have to tackle this from the early days to have an impact so that it doesn’t spin out of control.”

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