Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration

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. Astrocytes are essential for neuronal survival and function in the CNS but, under pathological conditions, they can adopt potentially harmful reactive states. This Review highlights how ‘omics’ technologies can enable the functional characterization of defined reactive astrocyte states in various pathological scenarios. 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