In Alzheimer's disease, fat droplets may form in the brain's immune cells, causing them to release neuron-damaging chemicals. This process is more likely to happen in people who carry the Alzheimer's genetic risk factor APOE ԑ4. Findings from this NIA-funded study, published in Nature, provide researchers with long-sought clues to understanding the disease and suggest a potential avenue for future treatment for some cases of Alzheimer's.

The idea that fat droplets may play a role in Alzheimer's has been around for many years. It was first raised by Dr. Alois Alzheimer in 1907 when he published a paper describing his original observations when studying the brains of people who had died from what would eventually be called Alzheimer's disease. He reported seeing several hallmarks of damage, including the presence of protein clusters called plaques and tangles, as well as lipid (fat) droplets in a type of brain cell, called glia. Although scientists have uncovered many clues about the harmful nature of plaques and tangles, there have been limited advances in knowledge about the potential role played by fat-filled glia.

In this study, a team of researchers led by scientists from Stanford University investigated whether the lipid droplets may primarily appear in certain types of cells called microglia, the brain's primary immune cells.

Initial experiments on human brain tissue confirmed that people who died with Alzheimer's had more lipid droplets than those who did not have the disease. Moreover, the researchers found correlations that support a role for the droplets in Alzheimer's. For example, people who had Alzheimer's and who carried two copies of the APOE ԑ4 gene variant tended to have more lipid droplets and lower scores on cognitive tests than those who carried a different version of the gene, APOE ԑ3.

Genetic analysis of the brain tissue samples suggested that microglia produced many of the lipid droplets. On average, microglia in the brains of people who had Alzheimer's showed greater levels of activity from ACSL1, a gene that controls droplet formation, than those who did not have the disease. The highest levels of ACSL1 activity were found in the microglia of people who had Alzheimer's and carried two copies of APOE ԑ4.

Lipid droplets are thought to help immune cells protect the body from bacteria and other invaders. Further genetic analysis suggested that the fat-filled microglia were in a similar defensive state. These cells appeared most often in the brains from people who had Alzheimer's and carried two copies of APOE ԑ4.

Other brain tissue experiments suggested that the defensive state may reflect a response to the damage caused by Alzheimer's. Most droplets appeared very closely - less than the width of thin human hair - to plaques made of beta-amyloid proteins.

This idea was also supported by experiments on human microglia grown in petri dishes. Treating microglia with beta-amyloid proteins caused a rise in the appearance of lipid droplets. The largest effects happened in cells that carried two copies of the APOE ԑ4 gene. In contrast, turning off the APOE gene blocked this reaction.

Next, the researchers showed how the reaction to beta-amyloid may in turn cause microglia to release harmful chemicals. To do this, they separated cells containing high lipid droplet levels from ones with low levels, grew each type in petri dishes, and then treated neurons grown separately in petri dishes with liquid from the microglia dishes.

Depending on the conditions, treating neurons with liquid from microglia containing high levels of droplets appeared to both turn on cell death gene activity and increase the presence of phosphorylated tau, a protein that forms the core of damaging tangles. The microglia that also carried two copies of the APOE ԑ4 gene produced the strongest effects. In contrast, treating neurons with liquid from microglia that had low droplet levels or ones that carried an inactive version of the APOE gene showed no signs of damage.

Treatment with liquid from microglia with high lipid levels also led to higher levels of lipids in neurons. Although more experiments are needed, the researchers hypothesized that beta-amyloid may not only trigger the accumulation of lipids in microglia, but also the transfer of those lipids to neurons.

Finally, the researchers showed how some drugs may counteract this reaction to beta-amyloid. Treating the microglia with an anti-cancer drug that is designed to block the activity of a gene that was found to be turned on by beta-amyloid reduced the appearance of fat droplets in the cells.

Overall, the results support the idea that fat-filled microglia may play a role in the damage caused by Alzheimer's, especially for those who carry two copies of the APOE ԑ4 gene.

This research was supported in part by NIA grants P01AG073082, P30AG19610, P30AG072980, P30AG062429, P30AG059307, R01AG064928, R01AG069453, R03AG071791, and T32AG000266.

Reference: Haney MS, et al. APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia. Nature. 2024;628(8006):154-161. doi:10.1038/s41586-024-07185-7.