Figure 9.

APOE targets cytoplasmic LDs via the ER and modulates LD composition and size. Schematic of our model of LD-associated APOE trafficking and function. (A) Normally, APOE is translocated into the lumen of the ER, where it assembles with nascent lipoprotein particles and is secreted. Under conditions that stimulate LD biogenesis, APOE subverts translocation via an unknown mechanism (retaining its signal peptide) and localizes to the cytoplasmic face of the ER membrane. It then moves onto LDs via membrane bridges between LDs and the ER. (B) On LDs, APOE is required to maintain triglyceride saturation and a dispersed LD size phenotype. In APOE4 cells, LDs are larger, accumulate highly unsaturated triglycerides, have impaired turnover, and are more sensitive to lipid peroxidation. We hypothesize that defects in the function of LD-associated APOE4 promote lipid dishomeostasis and sensitize astrocytes to stress, which could facilitate the progression of Alzheimer’s pathology.