When Microglia Eat Iron-Rich Cell Debris, They Explode

In Star Wars: The Empire Strikes Back, Harrison Ford’s character, Han Solo, is captured by enemies and immobilized inside a fictional metal alloy called carbonite. In the brains of people with dementia, something similar happens to the microglia — the brain’s immune cells — which are taken out of the action by iron. 

Studying 40 autopsied brains from people with Alzheimer’s and vascular dementia, Oregon Health & Science University scientists discovered that microglia die after ingesting iron-rich debris from other dying cells. These iron-rich bits are called myelin, an essential part of the insulating sheath that allows neurons to send electrical messages. While Han Solo was fortunate enough to be rescued, these microglia ultimately explode through a process called ferroptosis.   

“Everyone knows that microglia are activated to mediate inflammation,” senior author Dr. Stephen Back, neurologist and professor at the Oregon Health & Science University said in a press statement. “But no one knew that they were dying in such large numbers. It’s just amazing that we missed this until now.”

What triggers the process?

Conditions like high blood pressure, diabetes, or stroke are major risk factors for Alzheimer’s and may be to blame for the process — they all damage the brain’s blood vessels, making it harder to get oxygen and nutrients into the brain. The iron-rich myelin sheaths surrounding neurons are especially vulnerable to this process. 

The brain cells start losing their myelin, attracting microglia, which normally eat and digest cellular damage and debris. But they are poisoned by the high levels of iron, which causes the cell to explode through ferroptosis. 

“Ferroptosis is a recently described form of cell death that has not been appreciated until relatively recently,” Back told Being Patient. “ Important roles for ferroptosis are being uncovered in diverse conditions including cancer biology and neurogenerative disease including Parkinson’s disease.”

Since the microglia die, they can no longer do their job clearing beta-amyloid plaques and other toxic protein deposits or otherwise protect the brain. This breakdown in the cleaning process could kickstart neurodegeneration and cognitive decline. 

“The implications from our work is that drugs that block ferroptosis might be a promising new direction to promote the survival and activity of microglia,” Back said. 

A new drug approach may involve preventing microglia from eating up the iron-rich debris in the first place. Drugs traditionally used for multiple sclerosis avoid the breakdown of myelin and, in animal models, have shown the potential to slow the course of Alzheimer’s. Scientists are already interested in repurposing these drugs for the disease.

Other research has focused on targeting microglia, rather than amyloid or tau, to treat Alzheimer’s disease. Scientists are currently testing whether activating the TREM2 protein in these immune cells could also turbocharge their activity.

The TREM2 protein helps clear out or recycle debris in the brain, respond to infection, and deal with other forms of damage that may be present in Alzheimer’s. Drugmakers Alector and Abbvie are testing an antibody called AL002 that activates TREM2 in Phase 2 trials in the hopes that it will slow the progression of Alzheimer’s disease. They are also in the earliest stages of testing a newer antibody called AL044, leading to TREM2 activation. 

If these trials yield positive results, it could open the doors for a new class of microglia-targeting drugs.