APOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons

Abstract Lipid abnormalities are emerging as key pathogenic mechanisms in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Lewy body dementia. Astrocytes in the brain provide apolipoprotein E (APOE) proteins and influence neuronal metabolism and health. Using live-cell imaging and objective neurite imaging techniques, we induced cellular lipid load (cholesterol and triglycerides) by inhibiting the lysosomal cholesterol transport protein NPC1 in human neuron−astrocyte cocultures and examined the effects of CRISPR-edited APOE3 and APOE4 human astrocytes on the rescue of dystrophic neurites, where axons and dendrites of nerve cells become disfigured. APOE3, but not APOE4 or APOE knockout, astrocytes prevented cholesterol- and lipid-induced neurite damage in APOE4 neurons. In the media of APOE3 neuron−astrocyte cocultures, high-density lipoprotein−like particles were larger and presumably more lipidated than those in equivalent APOE4 cocultures. This discovery highlights that living APOE3 astrocytes control key biological mechanisms by physiologically enhancing lipid cellular homeostasis and rescuing lipid-induced neurite structural abnormalities relevant to Alzheimer's disease and neurodegenerative diseases.