From the WashU Newsroom…
People with specific mutations in the gene TREM2 are three times more likely to develop Alzheimer’s disease than those who carry more common variants of the gene. But until now, scientists had no explanation for the link.
New research in mice at Washington University School of Medicine in St. Louis indicates that the high-risk mutations in TREM2 cause an energy deficit in cells that clear away debris in the brain. When such cells are running on empty, they can’t protect neurons from harmful plaques that tend to collect in the brain as people get older.
“Everybody has some plaques, but the activity of these cells affects how much damage the plaques do,” said senior author Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology. “So if you have dysfunction in these cells, you have an accelerated process of neurodegeneration. If the cells are more functional, you can delay the process.”
The findings suggest that energizing the brain’s cleanup crew – made up of a kind of immune cell known as microglia – could reduce neurological damage and forestall the memory loss and confusion experienced by people with Alzheimer’s disease.
The study is published Aug. 10 in the journal Cell.
Amyloid beta is a sticky protein that neurons release as a byproduct of their normal functioning. The protein is harmless if swept away quickly, but when it starts forming plaques it can injure the neurons nearby.
Colonna and colleagues previously had shown that normal microglia surround and wall in the plaques, keeping the area of injury contained. Microglia from mice lacking TREM2, however, allow the plaques to spread and damage neurons more extensively.
To find out why microglia carrying certain TREM2 variants fail to do their job, Colonna, postdoctoral researcher Tyler Ulland, PhD, and MD/PhD student Wilbur Song and their colleagues studied microglia from mice genetically predisposed to develop amyloid plaques and lacking TREM2.
When they viewed the microglia under a microscope, they saw that the microglia were digesting and recycling their own proteins, a sign that their energy stores were running low.
With the aid of David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, the researchers also looked at microglia from people who had died of Alzheimer’s disease and carried high-risk TREM2 mutations. These cells, too, had been eating their own proteins.
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