MIT Scientists Reverse Alzheimer’s Gene Damage in Brain Cells

Neuroscientists at the Massachusetts Institute of Technology discovered how the major genetic risk factor for late-onset Alzheimer’s disease damages brain circuits. The gene variant, known as APOE4, prevents brain cells from properly wrapping neurons in a protective fatty layer called myelin. This fatty layer helps electrical signals travel quickly and efficiently through the brain.

Tracing the Cellular Pathway

The research team used advanced gene-editing techniques to study human brain cells in a laboratory setting. They found that the APOE4 gene suppresses a specific molecular chain of events known as Wnt signaling. When this signal is weak, support cells called oligodendrocytes fail to use their fats to insulate nerve fibers. Instead, the fats build up in unhelpful droplets inside the cells.

• Researchers used gene editing to test every protein-coding gene in human cells.
• Analysis showed that genes promoting Wnt activity were less accessible in APOE4 carriers.
• The team identified two competing proteins that regulate the Wnt pathway.

Testing a Potential Treatment

After pinpointing the pathway, the scientists tested an intervention to fix it. They used a chemical compound to block an overactive protein that suppresses Wnt signaling in cells carrying the APOE4 variant. When they applied this chemical to human cell cultures and to mice bred to model Alzheimer’s disease, the fatty droplets decreased. The cells resumed producing protective myelin around the nerve fibers.