Neurotoxic reactive astrocytes induce cell death via saturated lipids

Astrocytes can respond to diseases and injuries of the central nervous system by driving the death of neurons and mature oligodendrocytes through the delivery of long-chain saturated fatty acids contained in lipoparticles. Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease(1-6). Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor(5,6). Notably, instead of a protein, saturated lipids contained in APOE and APOJ lipoparticles mediate astrocyte-induced toxicity. Eliminating the formation of long-chain saturated lipids by astrocyte-specific knockout of the saturated lipid synthesis enzyme ELOVL1 mitigates astrocyte-mediated toxicity in vitro as well as in a model of acute axonal injury in vivo. These results suggest a mechanism by which astrocytes kill cells in the central nervous system.

Automated summary

Astrocytes respond to diseases and injuries in the central nervous system by releasing long-chain saturated fatty acids contained in lipoparticles, leading to the death of neurons and mature oligodendrocytes. The elimination of saturated lipids produced by astrocytes can mitigate astrocyte-induced toxicity, suggesting a mechanism by which astrocytes kill cells in the central nervous system.