Gene variant linked to Alzheimer’s disease may disrupt myelin production
AAmong people with Alzheimer’s disease, 40 and 65 percent have a gene variant called APOE4. Scientists have long known that the variant significantly increases the risk of developing the neurodegenerative disease, particularly when the person inherits copies from both parents, but they are still learning about the molecular mechanisms that explain APOE4‘s role.
A study published on November 16 in Nature suggests that one way APOE4 may contribute to Alzheimer’s disease by causing cholesterol to build up inside oligodendrocytes, reducing the cells’ ability to perform their main function: to make fatty myelin sheaths that protect neurons and help them transmit signals. Research further reveals that in mice with APOE4removing cholesterol plugs – the main ingredient of myelin – and allowing the substance to cross cell membranes, partially restored myelin production and improved cognition, suggesting a therapeutic target to fight Alzheimer’s disease .
“They show that one of the things that APOE fact, which has not been so well characterized before, is that it appears to influence lipid metabolism in oligodendrocytes,” explains
David Holtzman, a neurologist at Washington University in St. Louis, who was not involved in the work. Holtzman says that APOE4 has been shown by others to affect lipids and cholesterol in a number of different cell types, especially microglia and astrocytes“but no one to my knowledge has really looked so specifically at oligodendrocytes.”
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Oligodendrocyte precursors co-cultured with neurons in vitro, with myelin basic protein in green. APOE3 cells (left) shows signs of the increased amount of myelin, and APOE4 cells (center) show signs of reduced myelin. Treat APOE4 cells containing cyclodextrin appear to promote myelin formation (right).
BLANCHARD ET AL; NATURE
“Many biological pathways are disrupted by APOE4“, co-author of the study Li Huei Tsaineuroscientist at MIT’s Picower Institute for Learning and Memory, says The scientist. Because the APOE gene encodes a protein responsible for transporting lipids between cells, Tsai says the researchers decided to focus on how the variant disrupts the metabolism of cholesterol and other lipids.
Using transcriptomic profiling, the researchers compared post-mortem human brain tissue from people with and without Alzheimer’s disease and measured the level of expression of various genes in those with zero, one or two copies of APOE4 variant to reveal that ” APOE4 has a huge impact on gene expression,” says Tsai, especially on many genes that influence lipids. Performing similar oligodendrocyte profiling, she says, showed that genes associated with cholesterol making were significantly up-regulated in the cells, while genes associated with myelin production were down-regulated. .
“What we saw from the gene expression data was counterintuitive,” says study co-author Manolis Kellisa computational biologist at MIT’s Computer Science and Artificial Intelligence Laboratory, adding that because the gene clusters weren’t being regulated in the same direction, there seemed to be a signal mismatch.
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Transmission electron microscopy images of APOE4 mouse brain tissue, without (above) and with (below) cyclodextrin treatment. Darker borders indicate thicker myelin sheaths around axons.
BLANCHARD ET AL; NATURE
Digging deeper into the mystery, the researchers performed lipid analyzes in the brain tissue of people with at least one copy of APOE4 Where APOE3the The most common APOE variant, which is not associated with an increased risk of Alzheimer’s disease. The results indicated that APOE4 the brains had higher levels of cholesterol esters, which Tsai says are insoluble forms of cholesterol known to build up in cells. When researchers stained brain tissue from homozygous humans and mice to APOE4, they found that cholesterol droplets accumulated inside the oligodendrocytes of both. Meanwhile, cholesterol was found outside cells more frequently in samples with APOE3.
Researchers began to suspect that the APOE4 the variant impaired cholesterol transport across oligodendrocyte membranes. In imagining that oligodendrocytes function as myelin printers, the emerging hypothesis was that the cells had plenty of ink (cholesterol), but “the ink gets stuck inside the cartridge,” Kellis explains.
Check APOE4‘s association with reduced myelin production, the researchers conducted a variety of experiments. First, they induced pluripotent stem cells to form oligodendroglia, the precursors of oligodendrocytes, and then they co-cultured them with induced neurons in the lab. Typically, these co-cultured oligodendroglia begin to form myelin within weeks, Tsai says. The researchers noted this effect in the APOE3 co-culture, “but in APOE4 coculture, we have seen much-reduced . . . myelin basic protein signature,” she says, indicating less myelin production. Transmission electron microscopy of brain tissue also showed that mice APOE4 had fewer neurons with myelinated axons, and that neurons that were myelinated had thinner sheaths compared to APOE3 mouse.
The team then attempted to reduce cholesterol buildup and restore myelin production in vitro and in the APOE4 mice using cyclodextrin, a drug known to reduce the accumulation of intracellular cholesterol. APOE4 oligodendroglia-neuron cocultures treated with cyclodextrin for two weeks saw myelin increase to levels approaching APOE3 co-cultures. The researchers gave mice twice-weekly subcutaneous injections of the drug for 8 weeks, then compared their brain tissue to untreated one. APOE4 mouse. In the treated mice, less cholesterol accumulated in the oligodendrocytes and the researchers observed higher levels of myelin basic protein outside the cells, suggesting that the treatment improved both cholesterol flux and myelination. Finally, the researchers performed several cognitive tests on the mice, and “what we saw was that indeed it actually improves cognition,” Kellis says.
Holtzman says he’d like to see others confirm the results and he’s not yet convinced the results are clinically relevant to humans. “APOE4 has many mechanisms as to how it probably alters Alzheimer’s risk,” he says, “I’m not sure if that’s one of the most important or not. It’s really hard to say. It’s possible that changes in cholesterol and myelin contribute to the decline or degeneration associated with Alzheimer’s disease, he says, “but there are so many other things that APOE fact that we know it has a massive effect on Alzheimer’s pathology that is independent of any of these findings.
Holtzman writes in a follow-up email to The scientist that while APOE4 is linked to an increased risk of developing Alzheimer’s disease and more pronounced cognitive declines after the onset of symptoms, “these effects of APOE4 on Alzheimer’s disease are only observed in the presence of Alzheimer’s disease”, in particular the characteristic accumulation of amyloid plaques in the brain or tau protein tangles inside neurons. He adds that having APOE4 is not known to affect myelin levels in adults without Alzheimer’s disease, and to his knowledge no one has investigated this potential. Therefore, the findings of reduced myelin and cyclodextrin-mediated restoration of myelin and cognition in affected mice APOE4 but without Alzheimer’s disease, the pathology may or may not be clinically relevant to humans, he says.
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Tsai explains via email that previous fMRI studies linked the gene variant to reduced white matter, which is mostly composed of myelinated axons. She adds that the work of her and her colleagues highlights the need to study the mechanisms of Alzheimer’s risk that can begin before the disease and cognitive decline take hold. “Our results suggest opportunities for earlier therapeutic intervention,” she says. “I think that’s exactly what’s interesting about the study.”
Tsai says her lab will not be involved in any potential clinical trials to determine if cyclodextrin helps reduce symptoms in people with Alzheimer’s disease. Instead, she and her colleagues will continue to investigate the mechanisms explaining why the genetic variant causes this clogging effect in oligodendrocytes. “The more we know about how [cholesterol] gets there, more potential targets for drug discovery will emerge.