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One of the most important genetic risk factors for developing Alzheimer’s disease is the APOE4 gene, which is carried by almost half of all Alzheimer’s patients. A new study from MIT shows that this gene has far-reaching effects on the ability of brain cells to metabolize lipids and respond to stress.
In studies on human brain cells and yeast cells, the researchers found that the APOE4 gene severely impaired the ability of brain cells to carry out their normal functions. They also showed that treating these cells with additional choline, a widely available compound that is believed to be safe for human use, can reverse many of these effects.
The researchers hope their results will lead to clinical trials of choline in people who carry the APOE4 gene, who make up about 14 percent of the total population. Previous studies examining the effects of choline on cognition have shown mixed results. However, these studies were not specifically aimed at people with the APOE4 gene.
“What we would really like to see is whether in the human population, in these APOE4 carriers, if they take choline supplements in sufficient quantities, it would delay them or give them some protection against developing dementia or Alzheimer’s,” says Li-Huei Tsai, the director of the Picower Institute for Learning and Memory at MIT.
Tsai and the late Susan Lindquist, former director of MIT’s Whitehead Institute for Biomedical Research, are the lead authors on the study, which appears today in Science Translational Medicine. The newspaper’s three main authors are former Whitehead and MIT postdocs Grzegorz Sienski and Priyanka Narayan, and current MIT postdoc Julia Maeve Bonner.
The human gene for APOE or apolipoprotein E comes in three versions. While APOE4 is associated with a higher risk of Alzheimer’s disease, APOE2 is considered protective and APOE3, the most common variant, is neutral.
APOE is known to be involved in lipid metabolism, but its role in the development of Alzheimer’s is unclear, Tsai says. To learn more about this relationship, the researchers created human-induced pluripotent stem cells that carry either the APOE3 or the APOE4 gene in an otherwise identical genetic background. They then stimulated these cells to differentiate into astrocytes, the brain cells that produce most of the APOE.
APOE4 astrocytes showed dramatic changes in lipid processing compared to APOE3. There was a significant build-up of neutral lipids and cholesterol in APOE4 astrocytes. These astrocytes also accumulated droplets that contained a type of lipid called triglycerides, and these triglycerides had many more unsaturated fatty acid chains than normal. These changes all disrupt the normal lipid balance in the cells. The authors also noted APOE4-dependent lipid disorders in another important brain cell, microglia.
“When lipid homeostasis is compromised, many very important processes are affected, such as intracellular trafficking, vesicular trafficking, and endocytosis. Many of the essential functions of cells are compromised,” says Tsai.
“This balance is really important so that cells can perform normal functions such as creating membranes, etc., but also absorb stress,” says Bonner. “We believe that one of the events is that these cells are less able to absorb stress because they are already in an elevated state of lipid dysregulation.”
The researchers also found that yeast cells engineered to express the human version of APOE4 had many of the same defects. Using these cells, they performed a systematic genetic screening to determine the molecular basis of the defects observed in APOE4 cells. This screen showed that switching on a pathway that normally produces phospholipids, an essential part of cell membranes, can reverse some of the damage seen in APOE4 cells. This suggests that APOE4 somehow increases the need for phospholipid synthesis.
The researchers also found that growing APOE4 yeast cells on a very nutrient-rich growth medium helped them survive better than APOE4 yeast cells grown on the typical growth medium. Further experiments showed that the nutrient that helped APOE4 cells survive is choline, a building block that cells use to make phospholipids. The researchers then treated their human APOE4 astrocyte cells with choline to boost phospholipid synthesis and found that it also reversed much of the damage they had seen in these cells, including the accumulation of cholesterol and lipid droplets.
The researchers have now started investigating a mouse model of Alzheimer’s disease that was also developed to express the human APOE4 gene. They hope to investigate whether choline can help reverse some of the Alzheimer’s symptoms in these mice.
Choline occurs naturally in foods like eggs, meat, fish, and some beans and nuts. The minimum recommended intake of choline is 550 milligrams per day for men and 425 milligrams per day for women, but most people don’t consume that much, Tsai says. The new study offers preliminary evidence that people who carry the APOE4 gene can benefit from taking choline supplements, although clinical studies are needed to confirm it.
“Our results suggest that if you are an APOE2 or APOE3 carrier, you can deal with it even if you have some choline deficiency,” says Tsai. “But if you’re an APOE4 carrier and then you don’t take enough choline, the consequences are worse. The APOE4 carriers are more prone to choline deficiency.”
The researchers are investigating the link between the Alzheimer’s gene and COVID-19
H.-H. Wu el al., “Characterization of the first key steps of the oncogenic IL-17 receptor B signal for the targeted therapy of pancreatic cancer”, Science Translational Medicine (2021). stm.sciencemag.org/lookup/doi/… scitranslmed.abc2823 Provided by the Massachusetts Institute of Technology
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