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How microglia contribute to Alzheimer's disease | MIT News

One of the hallmarks of Alzheimer’s disease is decreased firing of some neurons in the brain. This contributes to the cognitive decline experienced by patients. A new study from MIT shows how a type of cell called microglia contributes to this slowing of neuronal activity.

This study found that microglia expressing the APOE4 gene, one of the strongest genetic risk factors for Alzheimer’s disease, are unable to metabolize lipids normally. This causes excess lipids to accumulate and interfere with the ability of nearby neurons to communicate with each other.

“APOE4 is a major genetic risk factor, and many people have it. If you get it wrong, it’s Alzheimer’s disease,” said Li-Huei Tsai, director of the Massachusetts Institute of Technology’s Picower Learning and Memory Institute and senior author of the study.

The findings suggest that if researchers could find a way to restore normal lipid metabolism in microglia, it might help treat some of the disease’s symptoms.

Matheus Victor, a postdoc at the Massachusetts Institute of Technology (MIT), was the lead author of the paper, and today cell stem cell.

lipid overload

Approximately 14% of the population carries the APOE4 variant, making it the most common genetic variant associated with late-onset non-familial Alzheimer’s disease. A person with one copy of APOE4 has a three-fold higher risk of developing Alzheimer’s disease, and a person with two copies has a ten-fold higher risk.

“If you look at this another way, if you look at the whole Alzheimer’s disease population, about 50% of them are APOE4 carriers. We don’t know yet what it will bring,” says Tsai.

The APOE gene also has two other forms known as APOE2, which is thought to be protective against Alzheimer’s disease, and the most common, APOE3, which is thought to be neutral. APOE3 and APOE4 differ by only one amino acid.

For several years, Tsai’s lab has studied the effects of APOE4 on various cell types in the brain. To do this, the researchers use induced pluripotent stem cells derived from human donors and engineer them to express specific versions of the APOE gene. These cells are stimulated to differentiate into brain cells such as neurons, microglia and astrocytes.

A 2018 study showed that APOE4 causes neurons to produce large amounts of the amyloid beta peptide 42. Amyloid beta peptide 42 is an Alzheimer’s-associated molecule that hyperactivates neurons. In this study, we found that APOE4 also affects microglia and astrocyte function, leading to cholesterol accumulation, inflammation, and failure to clear amyloid beta peptide.

A 2021 follow-up showed that there was a dramatic impairment in the ability of APOE4 astrocytes to process various lipids, leading to the accumulation of molecules such as triglycerides and cholesterol. They also showed that treatment of genetically engineered yeast cells expressing APOE4 with the dietary supplement choline, a building block of phospholipids, could reverse many of APOE4’s detrimental effects.

In their new study, the researchers wanted to investigate how APOE4 affects interactions between microglia and neurons. It has been shown to play an important role in regulating neural activity, including Microglia also scavenge the brain for signs of damage or pathogens, clearing away debris.

Researchers found that APOE4 inhibited the ability of microglia to metabolize lipids, preventing them from being removed from the environment. This leads to the accumulation of lipid molecules, especially cholesterol, in the environment.

“We know that neurons become less excitable in the later stages of Alzheimer’s disease, so we may be mimicking that in this model,” says Victor.

Lipid accumulation in microglia can also cause inflammation, and this type of inflammation is thought to contribute to the progression of Alzheimer’s disease.

brain scan
Three-dimensional human brain cultures, known as spheroids, were derived from induced pluripotent stem cells of patients with the Alzheimer’s disease risk variant APOE4. Here, neurons dissociated from spheroids are tagged with a genetic calcium reporter that allows a transient rise in calcium to be seen.Image credit: Researcher

Restore function

The researchers also showed that the effects of lipid overload can be reversed by treating APOE4 microglia with an agent called triacsin C, which prevents lipid droplet formation. Researchers found that exposure of APOE4 microglia to the drug restored normal communication between microglia and neighboring neurons.

“Perhaps restoration of lipid homeostasis, in which fatty acids are not accumulated extracellularly, can rescue APOE4 microglia from suppressing neuronal activity,” Victor says.

Although triacsin C can be toxic to cells and thus may not be suitable for use as a therapeutic agent for Alzheimer’s disease, researchers have found that other drugs for restoring lipid homeostasis In Tsai’s 2021 APOE4 study, she showed that choline can also help restore normal microglial activity.

“Lipid homeostasis is actually important for many cell types throughout the Alzheimer’s disease brain, so it’s not just a matter of microglia,” Victor says. It’s not an easy task, but we’re working through Colin, for example, and that’s a very interesting angle.”

Researchers are now further studying how microglia transition from a healthy state to a ‘lipid-laden’ inflammatory state, and hope to find ways to block that transition. Previous studies have shown that exposure to LED light that flickers at specific frequencies activates microglia and stimulates cells to resume normal function.

This study was funded by the National Institutes of Health, Howard Hughes Medical Institute Hannah H. Gray Postdoctoral Fellow, Robert A. and Lenny E. Belfer Family Foundation, Carol and Eugene Ludwig Family Foundation, Cure Alzheimer’s Fund, JPB . Foundation, Joseph P. DiSabato and Nancy E. Sakamoto, Donald A. and Glenda G. Mattes, Lester A. Gimpelson, Halis Family Foundation, Dolby Family, David Emmes, and Alan and Susan Patricof.