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      Neurotoxic reactive astrocytes are induced by activated microglia

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          Summary

          Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease but their role is poorly understood. Here we show that A1 reactive astrocytes are induced by classically-activated neuroinflammatory microglia. We show that activated microglia induce A1s by secreting Il-1α, TNFα, and C1q, and that these cytokines together are necessary and sufficient to induce A1s. A1s lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when A1 formation is blocked. Finally, we show that A1s are highly present in human neurodegenerative diseases including Alzheimer’s, Huntington’s, Parkinson’s, ALS, and Multiple Sclerosis. Taken together these findings explain why CNS neurons die after axotomy, strongly suggest that A1s help to drive death of neurons and oligodendrocytes in neurodegenerative disorders, and point the way forward for developing new treatments of these diseases.

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          Author and article information

          Journal
          0410462
          6011
          Nature
          Nature
          Nature
          0028-0836
          1476-4687
          22 March 2017
          18 January 2017
          26 January 2017
          26 July 2017
          : 541
          : 7638
          : 481-487
          Affiliations
          [1 ]Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA 94305, USA
          [2 ]Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, AUSTRALIA
          [3 ]Department of Psychiatry and Behavioral Sciences, Stanford University, School of Medicine, Stanford, CA 94305, USA
          [4 ]Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, 94143, USA
          [5 ]Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, 81675, GERMANY
          [6 ]Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
          [7 ]Department of Neurology & Neurological Sciences, Stanford University, School of Medicine, Stanford, CA 94305, USA
          [8 ]Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
          [9 ]Department of Microbiology and Immunology, Stanford University, School of Medicine, Stanford, CA 94305, USA
          [10 ]Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
          [11 ]Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
          [12 ]Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
          [13 ]Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
          [14 ]Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
          [15 ]Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
          [16 ]Departments of Pediatrics and Neurosurgery, University of California San Francisco, San Francisco, CA 94143, USA
          [17 ]Department of Paediatrics, University of Cambridge, Cambridge, CB2 0AH, UK
          Author notes
          Corresponding Author: Liddelow, Shane A ( liddelow@ 123456stanford.edu )

          BAB is a co-founder of Annexon Biosciences, Inc., a company working to make new drugs for treatment of neurological diseases.

          Article
          PMC5404890 PMC5404890 5404890 nihpa854157
          10.1038/nature21029
          5404890
          28099414
          7e49852d-8844-4f85-a645-a19e99168cb8

          Reprints and permissions information is available at www.nature.com/reprints.

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