Cell Reports. 2023 Mar 28
Ji-an Wei, Linglin Liu, Xichen Song, Bilian Lin, Jing Cui, Lanzhi Luo, Yuchu Liu, Shihua Li, Xiaojiang Li, Kwok-Fai So,Sen Yan, and Li Zhang
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AAV vector packaging rAAV2/9-hSyn-hTDP-43(M337V) Request Quote

Research Field: CNS

Keywords: Amyotrophic lateral sclerosis, TDP-43, Lycorine, Ubiquitin-proteasome system (UPS), Motor neurons

AAV Serotype: rAAV2/9

Routes of Administration: We first established a cortical model via bilateral infection of an AAV vector expressing mutant human TDP-43 (M337V)32 into mouse M1.


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.

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