Alzheimer’s risk gene disrupts nerve insulation in mice and human cells
The APOE4 gene is the most common genetic risk factor for Alzheimer’s disease. Researchers already knew it affects fat metabolism in the brain. Now they have clarified how: it disrupts the formation of the insulating sheath around nerve connections.
Nerve cells communicate via long extensions called axons. Those axons are normally wrapped in myelin, a fat-rich insulating layer that allows signals to travel quickly. Specialised brain cells called oligodendrocytes produce this myelin. In people and mice carrying the APOE4 gene, fat droplets accumulate inside those cells. The researchers found this happens because a signalling pathway called Wnt signalling is suppressed in those cells.
Fat signalling at the core of the problem
Wnt signalling normally controls how oligodendrocytes process and deploy fats for myelin production. In APOE4 carriers, that signalling is weakened. Fats accumulate inside the cell rather than being used to build myelin. This results in poorer insulation of nerve connections, impairing communication between neurons.
The researchers restored Wnt signalling in oligodendrocytes using a chemical inhibitor of a protein called GSK3b. This reduced fat droplet accumulation in cultured human cells and improved myelination in mice. Whether this could work as a treatment in humans has not yet been studied.
Accelerated brain deterioration in APOE4 carriers
Myelin around nerve fibres normally deteriorates somewhat with age, contributing to declining cognitive function later in life. If APOE4 accelerates that process by suppressing Wnt signalling, that may help explain why APOE4 carriers face a higher risk of Alzheimer’s. The study used both human cell cultures and a mouse model.
This adds a new mechanism alongside APOE4’s already known roles in inflammation and amyloid accumulation.
Search terms for further reading: APOE4 oligodendrocyte myelination, Wnt signalling brain aging, myelin loss Alzheimer’s risk