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

• Published in: Cell reports (Cambridge) Vol. 42; no. 3; p. 112240
• Main Authors: Wei, Ji-an, Liu, Linglin, Song, Xichen, Lin, Bilian, Cui, Jing, Luo, Lanzhi, Liu, Yuchu, Li, Shihua, Li, Xiaojiang, So, Kwok-Fai, Yan, Sen, Zhang, Li
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.03.2023; Elsevier
• Subjects: adipokine; Amyotrophic Lateral Sclerosis - genetics; Animals; CP: Neuroscience; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Humans; Mice; Mice, Transgenic; Microglia - metabolism; motor cortex; Neurodegenerative Diseases - metabolism; neuroinflammation; Physical Conditioning, Animal; physical exercise; TDP-43; motor cortex; physical exercise; adipokine; neuroinflammation; CP: Neuroscience; TDP-43
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112240

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. [Display omitted] •Mutant human TDP-43 leads to impaired E/I balance in the mouse motor cortex•Activated complement pathway drives microglial motility to disrupt PV interneuron•Treadmill exercise at the presymptomatic stage retards neuroinflammation•Adipocytic clusterin acts as a potential exerkine to relieve TDP-43 proteinopathy Physical exercise can retard the progression of neurodegenerative diseases. Using in vivo 2-photon imaging, Wei et al. show the modulation of microglial motility and related cortical circuitry activity by exercise under TDP-43 proteinopathy. Further molecular dissections reveal the adipocytic-derived clusterin to mediate the microglial complement pathway for relieving neuroinflammation.