The E4 allele of the apolipoprotein E gene (termed ApoE4) is the most prominent genetic risk factor for Alzheimer's disease (AD). As a protein that shuttles cholesterol and other lipids between and into cells, ApoE plays an important role in determining lipid balance. In their 3 March study, published in Science Translational Medicine, Dr. Gregor Sienzki, Prof. Li-Huei Tsai and colleagues probed the role of ApoE4 in human brain cells, showing that ApoE4 alters the expression of multiple genes involved in lipid metabolism, increasing the uptake of unsaturated lipids into these cells.
Brain cells called astrocytes are thought to be the main source of ApoE4 in the brain. Generating human astrocytes from induced pluripotent stem cells (iPSC), the researchers noted that ApoE4 astrocytes were laden with unsaturated lipids, containing far more lipid droplets than ApoE3 astrocytes. Mining gene expression data from people with different ApoE genotypes, they discovered that the expression of genes involved in the processing of lipids and cholesterol were upregulated in ApoE4 carriers, whereas genes involved in the breakdown of lipids were repressed. To probe the potential mechanisms causing the disruption in lipid composition, the researchers studied a model yeast system, using in-depth genetic screens to identify key proteins that might mediate the disruptive effects of ApoE4. One such protein, OP1, pointed to a potential role for choline deficiency in altering the lipid balance of ApoE4 brain cells. Choline is an essential nutrient, and one that is used to make lipid membranes for cells. By supplementing ApoE4 astrocytes with choline, researchers were able to correct the lipid disruption observed in these cells. Studies are now ongoing in ApoE4 animal models to evaluate choline supplementation as a potential remedy for ApoE4-induced lipid defects in AD.