Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration

ABSTRACT Despite advances in uncovering the mechanisms that underlie neuroinflammation and neurodegenerative disease, therapies that prevent neuronal loss remain elusive. Targeting of

disease-defining markers in conditions such as Alzheimer disease (amyloid-β and tau) or Parkinson disease (α-synuclein) has been met with limited success, suggesting that these proteins do

not act in isolation but form part of a pathological network. This network could involve phenotypic alteration of multiple cell types in the CNS, including astrocytes, which have a major

neurosupportive, homeostatic role in the healthy CNS but adopt reactive states under acute or chronic adverse conditions. Transcriptomic studies in human patients and disease models have

revealed the co-existence of many putative reactive sub-states of astrocytes. Inter-disease and even intra-disease heterogeneity of reactive astrocytic sub-states are well established, but

the extent to which specific sub-states are shared across different diseases is unclear. In this Review, we highlight how single-cell and single-nuclei RNA sequencing and other ‘omics’

technologies can enable the functional characterization of defined reactive astrocyte states in various pathological scenarios. We provide an integrated perspective, advocating cross-modal

validation of key findings to define functionally important sub-states of astrocytes and their triggers as tractable therapeutic targets with cross-disease relevance. KEY POINTS *

Neurodegenerative diseases are a group of serious and incurable conditions in which astrocytes both cause and respond to neuroinflammation. * A better understanding of how neuroinflammation

and astrocyte function are linked in neurodegeneration is likely to lead to new therapeutic strategies. * To gain this understanding, researchers are using a range of techniques and data

sets, including transcriptomic studies at the single-cell and single-nuclei levels, and the findings are being validated using both human and animal models across different stages of

neurodegenerative diseases. * Transcriptomic studies of reactive astrocytes in human and animal models of disease have revealed the co-existence of many pathology-related reactive sub-states

of astrocytes. * Future priorities for this research field include the determination of functional changes in transcriptomically defined reactive astrocyte sub-states. Access through your

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CRITICAL ROLES OF REACTIVE ASTROCYTES IN NEURODEGENERATION Article 10 April 2023 ASTROCYTE CONTRIBUTION TO DYSFUNCTION, RISK AND PROGRESSION IN NEURODEGENERATIVE DISORDERS Article 31

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references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, London, UK Rickie Patani * The Francis Crick Institute,

Human Stem Cells and Neurodegeneration Laboratory, London, UK Rickie Patani * Euan MacDonald Centre for MND, University of Edinburgh, Edinburgh, UK Giles E. Hardingham * UK Dementia

Research Institute at the University of Edinburgh, University of Edinburgh, Edinburgh, UK Giles E. Hardingham * Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK

Giles E. Hardingham * Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA Shane A. Liddelow * Department of Neuroscience & Physiology, NYU Grossman School of

Medicine, New York, NY, USA Shane A. Liddelow * Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA Shane A. Liddelow * Parekh Center for Interdisciplinary

Neurology, NYU Grossman School of Medicine, New York, NY, USA Shane A. Liddelow Authors * Rickie Patani View author publications You can also search for this author inPubMed Google Scholar *

Giles E. Hardingham View author publications You can also search for this author inPubMed Google Scholar * Shane A. Liddelow View author publications You can also search for this author

inPubMed Google Scholar CONTRIBUTIONS The authors contributed equally to all aspects of the article. CORRESPONDING AUTHOR Correspondence to Shane A. Liddelow. ETHICS DECLARATIONS COMPETING

INTERESTS R.P., G.E.H. and S.A.L. maintain a financial interest in AstronauTx. PEER REVIEW PEER REVIEW INFORMATION _Nature Reviews Neurology_ thanks K. Suk, who co-reviewed with A. Bhusal,

and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to

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terms of such publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Patani, R., Hardingham, G.E. & Liddelow, S.A. Functional roles of

reactive astrocytes in neuroinflammation and neurodegeneration. _Nat Rev Neurol_ 19, 395–409 (2023). https://doi.org/10.1038/s41582-023-00822-1 Download citation * Accepted: 11 May 2023 *

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