BNIP3L/NIX-mediated mitophagy limits Alzheimer disease pathology and preserves neuronal function

A genetic variant known as APOE4 significantly raises the likelihood of developing late-onset Alzheimer's disease, the most prevalent form of dementia. Recent research has uncovered the potential mechanism behind this variant's role in the condition: the accumulation of fat droplets, or lipids, in brain cells. Li-Huei Tsai, a neuroscientist at MIT and co-author of the study, explained that while the accumulation of two other proteins, amyloid-beta and tau, has been a primary focus in Alzheimer's research, the importance of lipid accumulation was previously overlooked.

The APOE4 variant, which increases the risk of late-onset Alzheimer's by three to 12 times, produces proteins that are less efficient at transporting fat within cells. Tsai's team has been investigating the impact of APOE4 on various cell types for nearly a decade. In their latest study, published in Cell Stem Cell, they found that APOE4 affects multiple cell types in the brain, including astrocytes, oligodendrocytes, and oligodendrocytes.

In astrocytes, APOE4 causes cholesterol buildup, while in oligodendrocytes, it results in cholesterol and fat accumulation. By using a drug to help cells eliminate excess cholesterol, the researchers observed improvements in myelin production and cognitive performance in lab mice. Their findings reveal that APOE4 disrupts the Wnt signaling pathway, a crucial process for cell-to-cell communication, in oligodendrocytes.

This disruption is linked to low levels of the DKK1 gene, which acts as a brake on the Wnt signaling system. Disabling DKK1 reduces the concentration of fat droplets in the cells. Lipid clearance and movement may be an essential therapeutic target in the treatment of Alzheimer's disease, according to the researchers. However, further research is necessary to determine how this approach can be safely and effectively applied to humans.