A new study from the Picower Institute for Learning and Memory at MIT has uncovered one of the main mechanisms by which the APOE4 gene variant, the biggest genetic risk factor for late-onset Alzheimer's disease, impairs brain circuit function. The research, published Oct. 15 in Cell Stem Cell, shows that APOE4 suppresses Wnt signaling in oligodendrocytes, the cells that insulate neurons with a fatty sheath called myelin. This disrupts myelination and causes lipid droplets to accumulate in the cells. By restoring Wnt signaling, the team was able to reverse the damage in both human cell cultures and in mice.
The study, led by Picower Professor Li-Huei Tsai and lead author Leyla Akay, used multiple experimental approaches to trace the disruption to a specific molecular pathway and then demonstrate a potential intervention.
Using CRISPR gene editing, the researchers systematically knocked out each protein-coding gene in cultures of human APOE4-carrying oligodendrocytes. The screen revealed that when genes promoting Wnt activity were absent, lipid droplets accumulated, and when genes suppressing Wnt were absent, droplets did not build up. In parallel, the team analyzed chromatin accessibility in human oligodendrocyte cultures and postmortem brain samples, comparing APOE4 carriers to those with the neutral APOE3 variant. That analysis showed that genes promoting Wnt signaling were less accessible in APOE4 carriers.
“This proof of principle of doing CRISPR screens for genetic modifiers of APOE4-associated lipid accumulation in a central nervous system cell type is very exciting,” Tsai said. “I think this type of screen not only provides new insights into cellular pathways contributing to lipid metabolism defects, but really also has the potential to provide new targets for drug development.”
Further experiments revealed that in APOE4 oligodendrocytes, levels of beta-catenin, which promotes Wnt signaling, were reduced, while levels of GSK3b, which suppresses it, were increased. The team tested a GSK3b inhibitor called CHIR99021. In human APOE4 oligodendrocyte cultures, the inhibitor reduced lipid droplets. In more complex organoid cultures combining APOE4 oligodendrocytes with neurons, it increased myelination and promoted axon growth. Finally, treating mice carrying APOE4 and modeling Alzheimer's tau pathology with CHIR99021 reduced lipid droplets and increased myelination in the hippocampus, a key brain region for memory.
Akay and Tsai said they plan to follow up on additional clues from the screen and explore GSK3b's link to tau phosphorylation, a hallmark of Alzheimer's. The study was funded by the National Institutes of Health, the Robert and Renee E. Belfer Family Foundation, and other sources.
Analysis
Why This Matters
- APOE4 is the strongest genetic risk factor for late-onset Alzheimer's, affecting about 25% of the population. Understanding how it disrupts brain function could lead to new treatments that target the underlying mechanism rather than just symptoms.
- The study identifies a specific, druggable pathway: restoring Wnt signaling via GSK3b inhibition reversed the cellular damage in both cell cultures and mice, offering a proof-of-concept for a potential therapy.
- The use of a genome-wide CRISPR screen in human oligodendrocytes demonstrates a powerful method to uncover disease mechanisms and drug targets in central nervous system cells.
Background
APOE4 is a variant of the apolipoprotein E gene, which is involved in lipid metabolism. Previous research, including work from the same Tsai lab in 2022, showed that APOE4 causes lipid droplet accumulation in oligodendrocytes and disrupts myelination. However, the underlying molecular pathway remained unclear. This new study fills that gap by identifying the suppression of Wnt signaling as the key driver, and shows that manipulating the GSK3b protein can restore normal function.
What to Watch
- Whether GSK3b inhibitors like CHIR99021 can be developed into safe and effective drugs for human clinical trials.
- Further research into other genes and pathways identified by the CRISPR screen that may also contribute to lipid metabolism defects.
- Studies investigating the connection between GSK3b and tau phosphorylation, which could link the findings to other aspects of Alzheimer's pathology.
Checked
12 claims in this story checked against 1 source: 10 supported.
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- SupportedThe MIT study identifies a key pathway through which APOE4 disrupts neuron insulation.MIT News: “A new study led by neuroscientists at the Picower Institute for Learning and Memory at MIT provides several lines of evidence to implicate a specific molecular pathway in that disruption”
- SupportedResearchers restored myelination by targeting the molecular mechanism in lab experiments.MIT News: “When the researchers restored Wnt signaling in APOE4-carrying oligodendrocytes, myelination rebounded, both in human cell cultures and in mice modeling Alzheimer’s.”
- SupportedAPOE4 suppresses Wnt signaling in oligodendrocytes, disrupting myelination and causing lipid droplets to accumulate.MIT News: “The study, published Oct. 15 in Cell Stem Cell , shows that APOE4 leads to a suppression of “Wnt” signaling in the oligodendrocyte cells that provide neurons with a fatty insulation, called myelin. When Wnt signaling is deficient, they showed, the cells accumulate droplets of lipids rather than deploying fats to properly myelinate the neurons’ axon branches.”
- SupportedThe study was published Oct. 15 in Cell Stem Cell.MIT News: “The study, published Oct. 15 in Cell Stem Cell , shows that APOE4 leads to a suppression of “Wnt” signaling”
- SupportedTsai said, “This proof of principle of doing CRISPR screens for genetic modifiers of APOE4-associated lipid accumulation in a central nervous system cell type is very exciting.”MIT News: ““This proof of principle of doing CRISPR screens for genetic modifiers of APOE4-associated lipid accumulation in a central nervous system cell type is very exciting,” says Tsai”
- SupportedTsai said, “I think this type of screen not only provides new insights into cellular pathways contributing to lipid metabolism defects, but really also has the potential to provide new targets for drug development.”MIT News: ““I think this type of screen not only provides new insights into cellular pathways contributing to lipid metabolism defects, but really also has the potential to provide new targets for drug development.””
- Sources say otherwiseThe CRISPR screen found that lipid droplets did not build up when genes suppressing Wnt were absent.MIT News: “The screen showed that when genes promoting Wnt activity in oligodendrocytes were lacking, lipid droplets accumulated, and that when genes suppressing Wnt were lacking, lipid droplets were, too.”
- SupportedChromatin analysis of human oligodendrocyte cultures and postmortem brain samples found Wnt-promoting genes were less accessible in APOE4 carriers than in APOE3 carriers.MIT News: “The chromatin analysis showed that genes promoting Wnt signaling were less accessible in APOE4 carriers.”
- Partly supportedIn APOE4 oligodendrocytes, beta-catenin levels were reduced and GSK3b levels were increased.MIT News: “The team found that in APOE4 oligodendrocytes compared to APOE3 ones, there was reduced beta-catenin expression and excessive GSK3b expression.”
- SupportedThe GSK3b inhibitor CHIR99021 reduced lipid droplets in human APOE4 oligodendrocyte cultures.MIT News: “In APOE4 oligodendrocytes, they showed that inhibiting GSK3b with a chemical called CHIR99021 reduced droplets.”
- SupportedIn organoid cultures combining APOE4 oligodendrocytes with neurons, the inhibitor increased myelination and promoted axon growth.MIT News: “In more complex “organoid” cultures combining APOE4 oligodendrocytes with neurons, they found that inhibiting GSK3b increased myelination and promoted the growth of neural axons.”
- SupportedIn mice carrying APOE4 and modeling Alzheimer’s tau pathology, CHIR99021 reduced lipid droplets and increased myelination in the hippocampus.MIT News: “The treated mice exhibited a reduction in lipid droplets in the hippocampus of the brain, a key memory-making region. Moreover, they also showed increased myelination there, compared to untreated controls.”