GNPS Neurotoxic reactive astrocytes induce cell death via saturated lipids

Astrocytes are essential regulators of the central nervous systems response to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease. There has been intense interest in identifying the putative toxic factor(s) secreted by astrocytes. Here, we report a biochemical approach to isolate the astrocyte-derived toxic factor. Unexpectedly, instead of a protein, we found saturated lipids contained in ApoE/ApoJ lipoparticles as components of astrocyte-mediated toxicity in vitro and in vivo. Eliminating the formation of long-chain saturated lipids by astrocyte cell-type-specific knockout of the saturated lipid synthesis enzyme ELOVL1 mitigates astrocyte-mediated toxicity in vitro as well as in an acute axonal injury model in vivo. These results suggest a new mechanism by which astrocytes kill cells in the CNS.