A recent study funded by the National Institute on Aging (NIA) has identified a new therapeutic potential in the treatment of Alzheimer’s disease by removing a specific genetic variant in mouse neurons. The study, published in Nature Aging, focuses on the APOE ε4 gene, which is considered the strongest genetic risk factor for Alzheimer’s.
The research team from the Gladstone Institutes investigated the role of the APOE ε4 gene in neurons, the cells responsible for transmitting signals in the nervous system. Through genetic engineering, they removed the APOE ε4 gene from mice neurons that already carried a disease-causing variant in the tau protein, known for forming damaging tangles in the brains of Alzheimer’s patients.
The removal of the APOE ε4 gene from neurons resulted in a reversal of many pathological hallmarks associated with Alzheimer’s disease. The damage typically observed in the brains of mice with the tau variant was significantly reduced. Cell death and the spread of tangles in the hippocampus, a brain region often affected by Alzheimer’s, were reduced. Additionally, the loss of myelin, the protective insulation around nerves, which is commonly observed in Alzheimer’s, was mitigated by the removal of neuronal APOE ε4, restoring myelinating cells to levels seen in healthy mice.
Furthermore, the removal of neuronal APOE ε4 also decreased the presence of “reactive” glial cells, which can contribute to neurodegeneration. In a healthy brain, glial cells support neurons, but in Alzheimer’s, they can become unhealthy and reactive. By removing APOE ε4 from neurons, the levels of reactive glial cells were reduced to those seen in healthy mice.
The study also found that removing the APOE ε4 gene in neurons altered the genetic activity of various brain cell types, shifting them from a damaging state to a protective state.
These findings provide new insights into the role of the APOE ε4 gene in Alzheimer’s disease and suggest that targeting this genetic variant in neurons could hold therapeutic potential for treating the disease. Further research is needed to explore the applicability of these findings in human patients.