ApoE4 impairs astrocyte lipid droplet formation via endolysosomal dysfunction

SUMMARY An important component of neuron-glia coupling is the transport and delivery of neuron-derived lipids to glial lipid droplets. This pathway is important as failure to store incoming lipids in glial lipid droplets exacerbates neurodegeneration. ApoE4, a risk factor for Alzheimer’s disease, impairs this transport pathway. But how ApoE4 affects lipid trafficking in glia and whether these alterations can be restored is poorly understood. Here, we demonstrate that ApoE4 particles impair endolysosomal function and promote lipofuscin formation in cultured primary astrocytes, thereby disrupting the trafficking of lipids for storage into lipid droplets. Lipid droplets, however, can be recovered by preventing lysosomal impairment with PCSK9, a secreted protein that prevents LDLR recycling and reduces ApoE4 internalization. Lipid droplets are similarly recovered in the presence of ApoE4 by repairing endolysosomal function. Our findings reveal new insight into how ApoE4 dysregulates lipid storage while uncovering new mechanisms to correct these defects. Graphical Abstract