The APOE4 gene variant, a major genetic risk factor for late-onset Alzheimer's disease, disrupts the functioning of brain neural circuits. A new study by scientists at MIT sheds light on how this happens: the APOE4 gene impairs the process of neuron insulation by a fatty sheath that optimizes their electrical transmission.
The researchers discovered that APOE4 suppresses the Wnt signaling pathway in oligodendrocyte cells. These cells are responsible for creating the myelin sheath – a fatty "insulator" that speeds up nerve impulse transmission. When Wnt signaling is disrupted, oligodendrocytes accumulate fat droplets instead of using them to form myelin. This leads to defective neuron insulation, which in turn affects brain function.
Most importantly, the researchers were able not only to identify this mechanism but also to demonstrate its reversibility. By restoring Wnt signaling in cells carrying APOE4, they achieved a resumption of myelination. This was shown in both human cell cultures and in experiments on mice modeling Alzheimer's disease. A key element in this process turned out to be the inhibition of the enzyme GSK3b, whose excessive activity in APOE4 cells suppresses Wnt signaling. Treating mice with a GSK3b-inhibiting drug led to a reduction in lipid accumulation and an increase in myelination in the hippocampus – a brain region critically important for memory.
This discovery is of great significance. It not only reveals the molecular reasons why APOE4 increases the risk of Alzheimer's disease but also points to a specific target for the development of new drugs. The ability to restore myelination by targeting GSK3b opens the way to creating therapies aimed at protecting neural connections and slowing disease progression. This is a step towards not just fighting symptoms, but addressing the root causes at the cellular level.