Neuroscientists at MIT's Picower Institute for Learning and Memory have traced one way the APOE4 gene variant, the biggest genetic risk factor for late-onset Alzheimer's disease, undermines the brain's wiring.
The study, published Oct. 15 in Cell Stem Cell and highlighted by MIT News on Oct. 28, focuses on myelin, the fatty sheath that insulates neurons and speeds their electrical signals.
What they found
The team found that APOE4 suppresses Wnt signaling in oligodendrocytes, the brain cells that produce myelin. When that signaling falls short, the cells pile up droplets of lipids instead of using those fats to wrap the branches of neurons, according to MIT.
A proof-of-concept fix
The researchers then targeted an enzyme called GSK3b. In APOE4 oligodendrocytes, blocking it with a chemical called CHIR99021 reduced the lipid droplets. In organoid cultures that combined those cells with neurons, it increased myelination and promoted the growth of axons.
As a final test, they treated mice carrying APOE4 and modeling Alzheimer's tau pathology. The treated mice had fewer lipid droplets and more myelin in the hippocampus, a key memory region, than untreated mice.
What it means
MIT describes the result as a proof of concept, not a treatment. The work points to restoring Wnt signaling and myelination as a possible strategy that would need much more testing before it could reach patients.