2. Academic Validation
  3. Physical exercise modulates the microglial complement pathway in mice to relieve cortical circuitry deficits induced by mutant human TDP-43

Physical exercise modulates the microglial complement pathway in mice to relieve cortical circuitry deficits induced by mutant human TDP-43

  • Cell Rep. 2023 Mar 15;42(3):112240. doi: 10.1016/j.celrep.2023.112240.
Ji-An Wei 1,  Linglin Liu 1,  Xichen Song 1,  Bilian Lin 1,  Jing Cui 1,  Lanzhi Luo 1,  Yuchu Liu 1,  Shihua Li 2,  Xiaojiang Li 2,  Kwok-Fai So 3,  Sen Yan 4,  Li Zhang 5
Affiliations

Affiliations

  • 1 Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China.
  • 2 Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; Guangdong Key Laboratory of Non-Human Primate Models, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China.
  • 3 Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; State Key Laboratory of Brain and Cognitive Science, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou 510515, China; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510300, China; Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao 266000, China.
  • 4 Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; Guangdong Key Laboratory of Non-Human Primate Models, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China. Electronic address: 231yansen@jnu.edu.cn.
  • 5 Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou 510515, China; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510300, China; Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao 266000, China. Electronic address: zhangli@jnu.edu.cn.
PMID: 36924491 DOI: 10.1016/j.celrep.2023.112240
Abstract

The aggregation of TAR DNA binding protein 43 kDa (TDP-43) is related to different neurodegenerative diseases, which leads to microglial activation and neuronal loss. The molecular mechanism driving neuronal death by reactive microglia, however, has not been completely resolved. In this study, we generated a mouse model by overexpressing mutant human TDP-43 (M337V) in the primary motor cortex, leading to prominent motor-learning deficits. In vivo 2-photon imaging shows an active approach of microglia toward parvalbumin interneurons, resulting in disrupted cortical excitatory-inhibitory balance. Proteomics studies suggest that activation of the complement pathway induces microglial activity. To develop an early interventional strategy, treadmill exercise successfully prevents the deterioration of motor dysfunction under enhanced adipocytic release of clusterin to block the complement pathway. These results demonstrate a previously unrecognized pathway by which TDP-43 induces cortical deficits and provide additional insights for the mechanistic explanation of exercise training in disease intervention.

Keywords

CP: Neuroscience; TDP-43; adipokine; motor cortex; neuroinflammation; physical exercise.

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