One of the hallmarks of Alzheimer’s disease is a reduction in the firing of certain neurons in the brain, which contributes to the cognitive decline that patients experience. A new study from MIT shows how a form of cell called microglia contributes to this slowing of neuronal activity.
The study found that the microglia that express the APOE4 gene, one of the most potent genetic risk factors for Alzheimer’s disease, cannot metabolize lipids normally. This leads to an accumulation of excess lipids which interferes with the ability of neighboring neurons to communicate with each other.
“APOE4 is a major genetic risk factor, and many people carry it. So the hope is that by studying APOE4 it will also provide a broader picture of the fundamental pathophysiology of Alzheimer’s disease and the fundamental cellular processes that must go wrong to lead to Alzheimer’s disease.” , explains Li-Huei Tsai, director of the Picower Institute for Learning and Memory at MIT and lead author of the study.
The results suggest that if the researchers could find a way to restore normal lipid metabolism in microglia, this could help treat some of the symptoms of the disease.
MIT put up-doctoral student Matheus Victor is the lead author of the paper, which appears today in Mobile Stem Cell.
Approximately 14% of the population has the APOE4 variant, making it the most common genetic variant linked to the disease non-familial Alzheimer’s disease the late onset. People who carry one copy of APOE4 have a three times higher risk of developing Alzheimer’s disease, and people who carry two copies have a ten times higher risk.
“If you look at it another way, if you look at the entire population with Alzheimer’s disease, approximately 50% of them are carriers of APOE4. So it’s a very serious risk, but we still don’t know why this APOE4 allele poses such a risk,” says Tsai.
The APOE gene also exists in two other forms, called APOE2, which is thought to be protective against Alzheimer’s disease, and the more common form, APOE3, which is considered neutral. APOE3 and APOE4 differ by only one amino acid.
For several years, Tsai’s lab has studied the effects of APOE4 on a variety of cell styles in the brain. To do this, researchers use induced pluripotent stem cells, derived from human donors, and modify them to express a specific version of the APOE gene. These cells can then be stimulated to differentiate into brain cells, including neurons, microglia, and astrocytes.
In a study by 2018, they showed that APOE4 causes neurons to produce large amounts of beta-amyloid peptide , a molecule related to Alzheimer’s disease which makes neurons hyperactive. This study found that APOE4 also affects microglia and astrocyte function, leading to cholesterol buildup, inflammation, and inability to clear beta-amyloid peptides.
Follow-up by 2021 showed that APOE4 astrocytes have dramatic alterations in their ability to process a variety of lipids, leading to an accumulation of molecules such as triglycerides, as well as cholesterol. In this posting, the researchers also showed that treating modified yeast cells expressing APOE4 with choline, a dietary supplement that is a building block of phospholipids, could reverse many of the damaging effects of APOE4.
In their new study, the researchers wanted to investigate how APOE4 affects the interactions between microglia and neurons. Recent research has shown that microglia play a significant role in modulating neuronal activity, including their ability to communicate within neuronal assemblies. Microglia also cleans the brain for signs of damage or pathogens, and removes debris.
Researchers have found that APOE4 disrupts the ability of microglia to metabolize lipids and prevents them from removing lipids from their environment. This leads to an accumulation of fatty molecules, especially cholesterol, in the environment. These fatty molecules bind to a specific type of potassium channel embedded in the cell membranes of neurons, which suppresses neuron firing.
“We know that in advanced stages of Alzheimer’s disease, the excitability of neurons is reduced, so we can mimic that with this model,” says Victor.
Lipid accumulation in microglia can also lead to irritation, the researchers found, and this type of inflammation may contribute to the development of Alzheimer’s disease.
Researchers have also shown that they can reverse the effects of lipid overload by treating APOE4 microglia with a drug called Triacsin C, which interferes with the formation of lipid droplets. When APOE4 microglia were exposed to this drug, researchers found that the normal interaction between microglia and neighboring neurons was restored. neuronal activity by APOE4 microglia, likely through the restoration of lipid homeostasis, where fatty acids no longer accumulate extracellularly,” says Victor.
The Triacsin C can be toxic to cells, so it probably wouldn’t be suitable as a drug to treat Alzheimer’s disease, but researchers hope that other approaches to restoring lipid homeostasis could help fight the disease. In Tsai’s APOE4 study in 2021, she showed that choline also helps restore normal microglia activity.
“Lipid homeostasis is actually critical for a number of cell types in the Alzheimer’s disease brain, so it’s not just a microglia issue,” says Victor . “The dilemma is how to restore lipid homeostasis in multiple cell types. It’s not an easy task, but we’re tackling that with choline, for example, which could be a really interesting angle.”
Researchers are now studying further detail how microglia transition from a healthy to an inflammatory “lipid-laden” state, in hopes of discovering ways to block this change. In previous studies on mice, they have shown that exposure to flickering LED light at a specific frequency can help rejuvenate microglia, stimulating the cells to resume their normal functions.
Research was funded by the Countrywide Institutes of Overall health, the Howard Hughes Medical Institute Hanna H. Gray Postdoctoral Fellowship, the Robert A. and Renee E. Belfer Household Foundation, the Carol and Eugene Ludwig Spouse and children Basis, the Get Rid of Alzheimer’s Fund, the JPB Foundation, Joseph P. DiSabato and Nancy E. Sakamoto, Donald A. and Glenda G. Mattes, Lester A. Gimpelson, the Halis Relatives Foundation, the Dolby family, David Emmes and Alan and Susan Patricof.