For decades, scientists believed fat in the brain was little more than a by-product of neurodegenerative diseases like Alzheimer’s.
But new research from Purdue University is overturning that assumption, showing that excess fat inside the brain’s immune cells actually weakens their ability to fight the disease.
The study, published in Immunity, focuses on microglia, the brain’s resident immune cells.
Under normal conditions, microglia act as housekeepers, clearing away harmful proteins such as amyloid beta and tau that are strongly linked to Alzheimer’s disease.
But the research team, led by chemistry professor Gaurav Chopra, found that when these immune cells take in too much fat, they become clogged and sluggish, leaving the brain more vulnerable.
Images of Alzheimer’s brains revealed that microglia closest to amyloid beta plaques contained twice as many fat droplets as cells farther away. These fat-laden immune cells cleared about 40% less amyloid beta than healthy microglia. Chopra’s team traced the problem back to how microglia handle fatty acids.
Instead of using them as energy, diseased microglia were storing them as long-term fat. The key culprit was an enzyme called DGAT2, which normally helps convert fatty acids into stored fat. In Alzheimer’s brains, DGAT2 wasn’t breaking down as it should, leading to a harmful buildup.
This discovery helps explain why immune cells in the brain fail as Alzheimer’s progresses. “We showed that amyloid beta is directly responsible for the fat that forms inside microglia,” Chopra said. “Because of these fatty deposits, microglial cells become dysfunctional—they stop clearing amyloid beta and stop doing their job.”
The team tested potential solutions in animal models, using molecules to either block DGAT2’s activity or speed up its breakdown. Both approaches reduced fat buildup, restored microglial function, and improved markers of brain health. By targeting fat metabolism, the researchers believe it may be possible to revive the brain’s natural defenses against Alzheimer’s.
This work builds on Chopra’s earlier studies, which linked fat accumulation in other brain cells to aging and neurodegeneration. He calls the discovery part of a “new lipid model of neurodegeneration,” where the specific types of fat that accumulate inside brain cells could define different brain diseases.
While most Alzheimer’s treatments have focused on directly targeting amyloid plaques or tau tangles, Chopra argues that restoring the health of immune cells may prove more effective. “Reducing the accumulation of fat in the diseased brain is the key,” he said. “By restoring microglial function, we may be able to maintain balance in the brain and help it fight disease the way it’s supposed to.”
The findings open the door to new therapies that target lipid metabolism, potentially giving researchers a fresh way to combat one of the most devastating diseases of aging.
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Source: Purdue University.
