Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases.
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We thank R. Vance (UC Berkeley) for gifting Il-1a-/- mice and E. R. Stanley (Albert Einstein College of Medicine) for gifting Csf1r-/- mice. This work was supported by grants from the National Institutes of Health (R01 AG048814, B.A.B.; RO1 DA15043, B.A.B.; P50 NS38377, V.L.D. and T.M.D.) Christopher and Dana Reeve Foundation (B.A.B.), the Novartis Institute for Biomedical Research (B.A.B.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (B.A.B.), the JPB Foundation (B.A.B., T.M.D.), the Cure Alzheimer’s Fund (B.A.B.), the Glenn Foundation (B.A.B.), the Esther B O’Keeffe Charitable Foundation (B.A.B.), the Maryland Stem Cell Research Fund (2013-MSCRFII-0105-00, V.L.D.; 2012-MSCRFII-0268-00, T.M.D.; 2013-MSCRFII-0105-00, T.M.D.; 2014-MSCRFF-0665, M.K.). S.A.L. was supported by a postdoctoral fellowship from the Australian National Health and Medical Research Council (GNT1052961), and the Glenn Foundation Glenn Award. L.E.C. was funded by a Merck Research Laboratories postdoctoral fellowship (administered by the Life Science Research Foundation). W.-S.C. was supported by a career transition grant from NEI (K99EY024690). C.J.B. was supported by a postdoctoral fellowship from Damon Runyon Cancer Research Foundation (DRG-2125-12). L.S. was supported by a postdoctoral fellowship from the German Research Foundation (DFG, SCHI 1330/1-1). T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors (N.P., M.K., V.L.D. and T.M.D.) acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation’s Parkinson’s Disease Program M-2014. We thank the Stanford Alzheimer’s disease research Centre (AG047366), the Stanford Health Care Brain Bank, The Arizona Ageing & Disability Resource Centers (AG019610) and Banner Sun Health for providing control and AD brain samples. We thank R. Reynolds and D. Gveric for providing control and MS brain samples from the UK Multiple Sclerosis Tissue Bank, funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland (registered charity 207495). We would like to thank O. Pletnikova and J. C. Troncoso from the Department of Pathology, Johns Hopkins University School of Medicine, for providing control and PD human sections. We thank the Neurological Foundation of New Zealand Human Brain Bank at the University of Auckland for Control and HD tissue sections for IHC analysis. We thank R. Myers at Boston University Medical Centre for control and HD tissue for q-RTPCR analysis. We thank J. Trojanoswki at the University of Pennsylvania Institute on Aging for AD and ALS tissue samples for in situ analysis. We thank A. Mosberger and A. Rosenthal for careful review of the manuscript. We thank T. Jessell and T. Maniatis for their insightful discussions on motor neuron subtypes. We thank V. and S. Coates for their generous support.
Extended data figures
This file contains Supplementary Figure 1, Supplementary Tables 1-6 and additional references.