Alzheimer’s Disease: Fat Metabolism in Microglia

• Alzheimer’s disease is a progressive brain disorder affecting memory, thinking, and behavior.

• The leading theory suggests Alzheimer’s is caused by the accumulation of harmful proteins like amyloid-beta and tau in the brain.

• Despite no cure, treatments are being developed to slow symptoms and improve quality of life.

• Researchers at Purdue University have discovered that fat metabolism in microglia may be a key driver of disease progression.

• Microglia, the brain’s resident immune cells, are responsible for clearing waste products and toxic proteins like amyloid-beta (A), which forms Alzheimer’s plaques.

• The study identified DGAT2, an enzyme that converts free fatty acids into triacylglycerols, the main component of lipid droplets, as a key player.

• The study found that microglia near amyloid plaques have high DGAT2 expression and are bloated with lipid droplets, particularly in the hippocampus, which is responsible for memory.

• The lipid overload caused by DGAT2 disruptions microglia’s ability to engulf and digest more A, leading to more fat and dysfunction.

• The researchers used genetically engineered mice and a pharmacological inhibitor and a custom-designed PROTAC-like degrader to test this build-up.

• Blocking DGAT2 reduced fat accumulation in microglia and restored their ability to clear amyloid plaques.

• The study’s findings may not be applicable to all forms or stages of Alzheimer’s due to the animal model used.