Apolipoprotein E-containing lipoproteins (LpE) are generated in the central nervous system by glial cells, primarily astrocytes, and are recognized as key players in lipid metabolism and transport in the brain. We previously reported that LpE protect retinal ganglion neurons from apoptosis induced by withdrawal of trophic additives (Hayashi, H., Campenot, R. B., Vance, D. E., and Vance, J. E. (2007) J. Neurosci. 27, 1933-1941). LpE bind to low density lipoprotein receptor-related protein-1 and initiate a signaling pathway that involves activation of protein kinase Cdelta and inhibition of the pro-apoptotic glycogen synthase kinase-3beta. We now show that uptake of LpE is not required for the neuroprotection. Experiments with inhibitors of phospholipase Cgamma1 and RNAi knockdown studies demonstrate that activation of phospholipase Cgamma1 is required for the anti-apoptotic signaling pathway induced by LpE. In addition, the protein phosphatase-2B, calcineurin, is involved in a neuronal death pathway induced by removal of trophic additives, and LpE inhibit calcineurin activation. LpE also attenuate neuronal death caused by oxidative stress. Moreover, physiologically relevant apoE3-containing lipoproteins generated by apoE3 knock-in mouse astrocytes more effectively protect neurons from apoptosis than do apoE4-containing lipoproteins. Because inheritance of the apoE4 allele is the strongest known genetic risk factor for Alzheimer disease, the reduced neuroprotection afforded by apoE4-containing LpE might contribute to the neurodegeneration characteristic of this disease.