Ralhan, I.; Do, A. D.; Bae, J.-Y.; Feringa, F. M.; Cai, W.; Chang, J.; Chik, K.; Lee, N. Y. J.; Gerry, C.; van der Kant, R.; Jackson, J.; Ricq, E. L.; Ioannou, M. S.

ApoE mediates the transport of lipids from neurons to glial lipid droplets. ApoE4, a major risk factor for Alzheimer\'s disease, impairs this transport pathway, increasing risk for neurodegeneration. ApoE2 and ApoE3 Christchurch (ApoE3Ch) variants confer resistance to developing the disease, yet little is known regarding how these protective variants affect lipid transport. Here, we explored how lipoprotein particles containing different ApoE isoforms affect neuronal health in vitro and in intact rodent hippocampi. We demonstrate that ApoE2 and ApoE3Ch particles protect neurons from ferroptosis by preferentially extracting peroxidated unsaturated lipids through the neuronal ABCA7 transporter. ApoE4 particles, on the other hand, exacerbate the effects of these toxic lipids leading to endolysosomal dysfunction. By reducing the peroxidated lipid burden in ApoE4 neurons, ApoE2 and ApoE3Ch particles rescue endolysosomal function and restore defects in neuronal activity. Our findings reveal a new mechanism by which ApoE2 and ApoE3Ch isoforms protect neurons from neurodegenerative disease.