Neurotoxic reactive astrocytes induce cell death via saturated lipids

Nature. 2021 Nov;599(7883):102-107. doi: 10.1038/s41586-021-03960-y. Epub 2021 Oct 6.


Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease1-6. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor5,6. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Astrocytes / chemistry*
  • Astrocytes / metabolism*
  • Cell Death / drug effects*
  • Culture Media, Conditioned / chemistry
  • Culture Media, Conditioned / toxicity
  • Fatty Acid Elongases / deficiency
  • Fatty Acid Elongases / genetics
  • Fatty Acid Elongases / metabolism
  • Female
  • Gene Knockout Techniques
  • Lipids / chemistry*
  • Lipids / toxicity*
  • Male
  • Mice
  • Mice, Knockout
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neurotoxins / chemistry
  • Neurotoxins / toxicity


  • Culture Media, Conditioned
  • Elovl1 protein, mouse
  • Lipids
  • Neurotoxins
  • Fatty Acid Elongases