Modulating mTOR-dependent astrocyte substate transitions to alleviate neurodegeneration

Traditional approaches to studying astrocyte heterogeneity have mostly focused on analyzing static properties, failing to identify whether subtypes represent intermediate or final states of reactive astrocytes. Here we show that previously proposed neuroprotective and neurotoxic astrocytes are transitional states rather than distinct subtypes, as revealed through time-series multiomic sequencing. Neuroprotective astrocytes are an intermediate state of the transition from a nonreactive to a neurotoxic state in response to neuroinflammation, a process regulated by the mTOR signaling pathway. In Alzheimer’s disease (AD) and aging, we observed an imbalance in neurotoxic and neuroprotective astrocytes in animal models and human patients. Moreover, targeting mTOR in astrocytes with rapamycin or shRNA mitigated astrocyte neurotoxic effects in neurodegenerative mouse models. Overall, our study uncovers a mechanism through which astrocytes exhibit neuroprotective functions before becoming neurotoxic under neuroinflammatory conditions and highlights mTOR modulation specifically in astrocytes as a potential therapeutic strategy for neurodegenerative diseases. The authors show that neuroprotective and neurotoxic astrocytes represent transitional cellular substates present during neuroinflammation and that targeting mTOR in astrocytes reduces neurotoxicity, suggesting a potential therapeutic strategy for neurodegenerative diseases.