Guttenplan KA, Weigel MK, Prakash P, Wijewardhane PR, Hasel P, Rufen-Blanchette U, Münch AE, Blum JA, Fine J, Neal MC, Bruce KD, Gitler AD, Chopra G, Liddelow SA, Barres BA. Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature. 2021 Nov;599(7883):102-107. Epub 2021 Oct 6 PubMed.

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  1. This is very interesting work unraveling a long-standing secret behind astrocyte-driven neurotoxicity. Activated astrocytes can acquire a neurotoxic phenotype, but the exact molecules that drive such neurotoxicity have been unknown. In this paper, Liddelow and colleagues have discovered the factors secreted by activated astrocytes to be saturated lipids contained in APOE and APOJ lipoparticles. Using in vitro systems, they have nicely demonstrated the specificity of the toxicity driven by these mediators.

    Astrocytic apoE has been shown to increase neurodegeneration in tau models of neurodegeneration (Wang et al., 2021) and astrocytes have been shown to play a key role in Rett syndrome neurodegeneration (Lioy et al., 2011) but the actual molecules driving the neurotoxicity phenotype were unknown. Saturated lipids identified in this new study may be the mediators of astrocyte toxicity in AD and Rett syndrome as well as in other neurological diseases.

    Future work should focus on examining the in vivo relevance of the saturated lipids contained in APOE and APOJ lipoparticles derived from astrocytes in different diseases.

    References:

    Wang C, Xiong M, Gratuze M, Bao X, Shi Y, Andhey PS, Manis M, Schroeder C, Yin Z, Madore C, Butovsky O, Artyomov M, Ulrich JD, Holtzman DM. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron. 2021 May 19;109(10):1657-1674.e7. Epub 2021 Apr 7 PubMed.

    Lioy DT, Garg SK, Monaghan CE, Raber J, Foust KD, Kaspar BK, Hirrlinger PG, Kirchhoff F, Bissonnette JM, Ballas N, Mandel G. A role for glia in the progression of Rett's syndrome. Nature. 2011 Jun 29;475(7357):497-500. PubMed.

    View all comments by Jonathan Kipnis

  2. In their tour de force study, Guttenplan, Liddelow and colleagues provide compelling evidence in vitro that inflammatory reactive astrocytes can release lipoparticles containing long-chain saturated fatty acids and APOE or APOJ lipoproteins, and that these particles mediate cytotoxicity of astrocyte-conditioned medium.

    This work opens up many interesting questions for future investigation: Given that most experiments were based on measuring toxicity to oligodendrocytes, is toxicity of inflammatory reactive astrocytes to neurons similarly mediated by lipoparticles? An in vivo toxicity assay showed only partial rescue of neurons when the synthesis of saturated long-chain fatty acids was disrupted, suggesting that additional mechanisms of toxicity may be relevant for neurons. 

    Our own recent results suggest that exocytosis of remodeled lysosomes from inflammatory reactive astrocytes mediates neurotoxicity, so we are excited to test whether saturated lipids may also be released via this pathway, or whether other lysosomal contents contribute to neurotoxicity.

    View all comments by Martin Kampmann

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