It was long believed that fat in the brain had little to do with neurodegenerative diseases.
But a new study from Purdue University challenges that idea, suggesting fat buildup in the brain’s immune cells may worsen diseases like Alzheimer’s.
Published in Immunity, the research reveals that too much fat in microglia—immune cells that clear brain waste—makes them less effective at fighting disease. Led by chemistry professor Gaurav Chopra, the study points to fat metabolism as a new pathway for potential Alzheimer’s treatments.
While most Alzheimer’s research focuses on the disease’s well-known protein build-ups—amyloid beta plaques and tau tangles—Chopra and his team are more interested in the fat-filled cells surrounding these areas.
In earlier studies, his team found that astrocytes, which support neurons, can release toxic fatty acids under disease conditions. Another study tied aging-related mitochondrial damage to fat accumulation in glial cells.
Chopra argues that treating Alzheimer’s may depend more on restoring microglial function than directly targeting protein plaques. “Reducing brain fat buildup may be key,” he said, “because it hinders the immune cells’ ability to protect the brain.”
His team examined brain tissue from Alzheimer’s patients and found that microglia near amyloid beta plaques had twice the fat droplets of those further away. These fat-heavy microglia cleared 40% less amyloid beta than normal microglia.
Digging deeper, they found that exposure to amyloid beta triggers microglia to produce too many free fatty acids. These are usually burned for energy, but in diseased brains, the fatty acids are instead stored as fat in large amounts—disabling the cells. This transformation relies on an enzyme called DGAT2, which is overly abundant in these damaged cells.
The team found that this enzyme wasn’t being made in higher amounts, but rather wasn’t breaking down properly. Its buildup caused microglia to shift from defense mode to fat storage mode, slowing their activity.
To fix this, researchers tested molecules that either blocked DGAT2 or sped up its breakdown. Both approaches restored microglial ability to clear plaques and improved brain cell health in animal models.
“This is a breakthrough,” said Chopra. “By stopping fat overload, we help immune cells return to their role of protecting the brain.”
This research also aligns with Purdue’s “One Health” initiative, which unites health research across people, animals, and plants.
Co-lead authors Priya Prakash and Palak Manchanda agree that linking fat metabolism to immune failure opens new doors. “Instead of just chasing proteins,” said Manchanda, “we can now target how the brain handles fat to fight Alzheimer’s.”
Chopra and his team hope that their findings pave the way for lipid-based therapies that support brain immunity and slow the advance of neurodegenerative diseases like Alzheimer’s.
The study is published in Immunity.
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