Researchers from MIT have identified a mechanism which causes a type of cells in the central nervous system called microglia that express the APOE4 gene to be one of the strongest genetic risk factors for Alzheimer’s disease.
The reduction in the firing of certain neurons in the brain including microglia is known as a hallmark of Alzheimer’s disease contributing to the rapid cognitive decline in patients. However, the underlying mechanisms of this defect are still largely unknown. A new study led by MIT has now identified a possible reason.
The findings published in Cell Stem Cell show that microglia that express the APOE4 gene cannot metabolize lipids efficiently leading to a buildup of excess lipids. This interferes with the cells´ ability to communicate with one another eventually leading to the well-known symptoms such as memory loss.
“APOE4 is a major genetic risk factor, and many people carry it, so the hope is that by studying APOE4, that will also provide a bigger picture of the fundamental pathophysiology of Alzheimer’s disease and what fundamental cell processes have to go wrong to result in Alzheimer’s disease,” said Li-Huei Tsai, neuroscientist at MIT’s Picower Institute for Learning and Memory and senior author of the study in a press statement.
Almost 14 percent of the population carries the APOE4 variant marking it as one of the most common genetic variants linked to late-onset Alzheimer’s disease. Carrying one copy of the gene results in a threefold higher risk of developing the disease while two copies increase the risk to up to ten times.
“If you look at this another way, if you look at the entire Alzheimer’s disease population, about 50 percent of them are APOE4 carriers. So, it’s a very significant risk, but we still don’t know why this APOE4 allele presents such a risk,” Tsai added.
The researchers showed that the lipid accumulation caused by the APOE4 gene may be reversed using several approaches in order to interfere with the formation of lipid droplets including a drug called Triacsin C with promising results. However, Triacsin C can have toxic effects on cells leading to the need for other therapeutic approaches.
“We can rescue the suppression of neuronal activity by APOE4 microglia, presumably through lipid homeostasis being restored, where now fatty acids are not accumulating extracellularly,” said Matheus Victor, postdoctoral fellow at MIT and co-author of the study.
“The question is, how do you restore lipid homeostasis across multiple cell types? It’s not an easy task, but we’re tackling that through choline, for example, which might be a really interesting angle.”
The researchers are now further investigating how microglia cells acquire the lipid accumulation defect in hopes of finding new ways to prevent late-onset Alzheimer’s disease.
