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Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration

Nature Reviews Neurology volume 19, pages 395–409 (2023)Cite this article

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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.

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Fig. 1: Physiological and reactive functions of astrocytes.
Fig. 2: Position of astrocytes within the inflammatory cascade.
Fig. 3: Methods for studying astrocyte reactivity.
Fig. 4: Disease-associated mutations that alter human astrocyte inflammatory responses and homeostatic functions.

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Authors and Affiliations

  1. Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, London, UK

    Rickie Patani

  2. The Francis Crick Institute, Human Stem Cells and Neurodegeneration Laboratory, London, UK

    Rickie Patani

  3. Euan MacDonald Centre for MND, University of Edinburgh, Edinburgh, UK

    Giles E. Hardingham

  4. UK Dementia Research Institute at the University of Edinburgh, University of Edinburgh, Edinburgh, UK

    Giles E. Hardingham

  5. Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK

    Giles E. Hardingham

  6. Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA

    Shane A. Liddelow

  7. Department of Neuroscience & Physiology, NYU Grossman School of Medicine, New York, NY, USA

    Shane A. Liddelow

  8. Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA

    Shane A. Liddelow

  9. Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, USA

    Shane A. Liddelow

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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

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