How the biggest Alzheimer’s risk gene disrupts the process of insulating neurons.
Neuroscientists at MIT's Picower Institute report that the APOE4 gene variant weakens Wnt signaling in myelin-producing brain cells, and that blocking a protein called GSK3b restored myelination in lab cultures and mice.
Researchers at the Picower Institute for Learning and Memory at MIT report that APOE4, the biggest genetic risk factor for late onset Alzheimer's disease, disrupts the insulation of neurons through a specific molecular pathway. The study was published Oct. 15 in Cell Stem Cell. Oligodendrocytes produce the fatty insulation, called myelin, which helps neurons transmit electrical signals efficiently.
The team, led by Picower Professor Li-Huei Tsai and lead author Leyla Akay, a former graduate student in Tsai's lab, found that APOE4 suppresses Wnt signaling in oligodendrocytes. When Wnt signaling was deficient, the cells built up droplets of lipids instead of using fats to myelinate axons. When the researchers restored Wnt signaling in APOE4-carrying oligodendrocytes, myelination rebounded in human cell cultures and in mice modeling Alzheimer's.
The researchers used two approaches to find the pathway. In one, a CRISPR screen knocked out each protein-coding gene, one at a time, in cultures of human APOE4 oligodendrocytes. In the other, they analyzed chromatin accessibility in human cell cultures and postmortem brain samples, comparing APOE4 with the neutral APOE3 variant. Genes that promote Wnt signaling were less accessible in APOE4 carriers. Tsai said, "There was a striking overlap between ATAC-seq and CRISPR screen results."
Further work showed that APOE4 oligodendrocytes had reduced beta-catenin, which promotes Wnt signaling, and excessive GSK3b, which suppresses it. In APOE3 cultures, raising GSK3b with a chemical called Dif3 increased lipid droplets. In APOE4 cultures, inhibiting GSK3b with CHIR99021 reduced them. In organoid cultures combining APOE4 oligodendrocytes with neurons, GSK3b inhibition increased myelination and promoted axon growth.
The team also treated mice that carried APOE4 and modeled Alzheimer's tau pathology with CHIR99021. Compared with untreated controls, the treated mice had fewer lipid droplets and more myelination in the hippocampus, a key memory-making region. The researchers describe GSK3b inhibition as a proof-of-concept strategy, and the results come from cell cultures and mice. Akay and Tsai said they plan to study how Wnt loss alters lipid metabolism and how GSK3b relates to tau phosphorylation. They have applied for a patent on the CRISPR screen results.
At a Glance
- The study appeared Oct. 15 in Cell Stem Cell, led by Li-Huei Tsai and Leyla Akay at MIT's Picower Institute.
- A CRISPR screen knocked out each protein-coding gene, one by one, in human APOE4 oligodendrocyte cultures.
- APOE4 oligodendrocytes had less beta-catenin and more GSK3b than APOE3 cells.
- In mice, the GSK3b inhibitor CHIR99021 reduced lipid droplets and increased myelination in the hippocampus.
Sources
This brief was written by Brightside Report from the reporting linked above. Spot an error? Request a correction.