Researchers have discovered a new aspect of Alzheimer’s and vascular dementia: ferroptosis-induced microglia cell death. This groundbreaking finding, highlighting the vulnerability of brain immune cells, opens new possibilities for dementia treatment and early intervention strategies.
The study highlights the degeneration of microglia in the brain caused by iron toxicity.
Scientists have identified a new avenue of cell death in Alzheimer’sAlzheimer's disease is a disease that attacks the brain, causing a decline in mental ability that worsens over time. It is the most common form of dementia and accounts for 60 to 80 percent of dementia cases. There is no current cure for Alzheimer's disease, but there are medications that can help ease the symptoms.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>Alzheimer’s disease and vascular dementia.
Recent research, led by scientists at Oregon Health & Science University and published in the journal Annals of Neurology, reveals for the first time that a form of cell death known as ferroptosis — caused by a buildup 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.
Methodology and Key Discoveries
The researchers conducted the study examining post-mortem human brain tissue of patients with dementia.
“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 studied myelin, the insulation-like protective sheath covering nerve fibers in the brain, including delays in forming myelin in premature infants. The new research extends that line of work by uncovering a cascading form of neurodegeneration triggered by the deterioration of myelin. They made the discovery using a novel technique developed by the study’s lead author Philip Adeniyi, Ph.D., a postdoctoral researcher in Back’s laboratory.
The researchers discovered that microglia degenerates in the white matter of the brain of patients with Alzheimer’s and vascular dementia.
Microglia Degeneration and Its Implications
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 new study, researchers found that microglia themselves are destroyed by the act of clearing iron-rich myelin — a form of cell death known as ferroptosis.
Given the intense scientific focus on the underlying cause of dementia in older adults, Back called 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,” 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.”
Co-author Kiera Degener-O’Brien, M.D., initially discovered the degeneration of microglia in tissue samples, Back said. 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, Back said.
In effect, the immune cells were 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.”
Potential Pharmaceutical Developments
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, Back said. He expects 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,” he said. “A discovery like ours will stimulate a lot of excitement in the pharmaceutical industry to develop therapeutically important compounds.”
He said 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,” Back said. “We have to tackle this from the early days to have an impact so that it doesn’t spin out of control.”
Reference: “Ferroptosis of Microglia in Aging Human White Matter Injury” by Philip A. Adeniyi, Xi Gong, Ellie MacGregor, Kiera Degener-O’Brien, Evelyn McClendon, Mariel Garcia, Oscar Romero, Joshua Russell, Taasin Srivastava, Jeremy Miller, C. Dirk Keene and Stephen A. Back, 21 August 2023, Annals of Neurology.
DOI: 10.1002/ana.26770
The research was supported by grants from the National Institute on Aging (AG065406, AG031892, U01 AG006781, and U19 AG066567 which supports the ACT study, p50 AG005136 and p30AG066509, which support the UW Alzheimer’s disease Research Center) of the National Institutes of HealthThe National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. Founded in 1887, it is a part of the U.S. Department of Health and Human Services. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program. With 27 different institutes and centers under its umbrella, the NIH covers a broad spectrum of health-related research, including specific diseases, population health, clinical research, and fundamental biological processes. Its mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>National Institutes of Health; the National Institute of Neurological Disorders and Stroke of the NIH (NS105984); and by the Nancy and Buster Alvord Endowment. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Source: SciTechDaily
