2. Academic Validation
  3. Modulating mTOR-dependent astrocyte substate transitions to alleviate neurodegeneration

Modulating mTOR-dependent astrocyte substate transitions to alleviate neurodegeneration

  • Nat Aging. 2025 Mar;5(3):468-485. doi: 10.1038/s43587-024-00792-z.
Liansheng Zhang # 1,  Zhengzheng Xu # 2,  Zhiheng Jia # 2 3,  Shicheng Cai # 2 3,  Qiang Wu 2 3,  Xingyu Liu 2,  Xinde Hu 4,  Tao Bai 2,  Yongyu Chen 2 3,  Tianwen Li 5,  Zhen Liu 2 6,  Bin Wu 7,  Jianhong Zhu 5,  Haibo Zhou 8 9
Affiliations

Affiliations

  • 1 Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. zhangls@ion.ac.cn.
  • 2 Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
  • 3 University of Chinese Academy of Sciences, Beijing, China.
  • 4 Genemagic Biosciences Co., Ltd., Shanghai, China.
  • 5 Fudan University Huashan Hospital, Department of Neurosurgery, National Center for Neurological Disorders, National Key Library for Medical Neurobiology, Shanghai Key Library of Brain Function and Regeneration, Institutes of Brain Science, MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
  • 6 Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China.
  • 7 Department of Neurology & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
  • 8 Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. hbzhou@ion.ac.cn.
  • 9 Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China. hbzhou@ion.ac.cn.
  • # Contributed equally.
PMID: 39779911 DOI: 10.1038/s43587-024-00792-z
Abstract

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.

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