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.

尽管在揭示神经炎症和神经退行性疾病背后的机制方面取得了进展，但预防神经元损失的治疗方法仍然难以捉摸。针对阿尔茨海默病（β-淀粉样蛋白和 tau 蛋白）或帕金森病（α-突触核蛋白）等疾病的疾病定义标记物的靶向取得了有限的成功，这表明这些蛋白质并不是孤立起作用的，而是形成病理网络的一部分。该网络可能涉及中枢神经系统中多种细胞类型的表型改变，包括星形胶质细胞，星形胶质细胞在健康中枢神经系统中具有主要的神经支持和稳态作用，但在急性或慢性不利条件下采取反应状态。对人类患者和疾病模型的转录组学研究揭示了星形胶质细胞许多假定的反应亚状态的共存。反应性星形细胞亚状态的疾病间甚至疾病内异质性已得到充分证实，但不同疾病之间共享特定亚状态的程度尚不清楚。在这篇综述中，我们重点介绍了单细胞和单核 RNA 测序以及其他“组学”技术如何能够在各种病理情况下对确定的反应性星形胶质细胞状态进行功能表征。我们提供了一个综合的视角，提倡对关键发现进行跨模式验证，以定义星形胶质细胞功能上重要的亚状态及其触发因素，作为具有跨疾病相关性的易处理的治疗靶点。