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Physical exercise modulates the microglial complement pathway in mice to relieve cortical circuitry deficits induced
Ji-An Wei1, Linglin Liu1, Xichen Song1
1Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China.
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.
Insights
Mutant TDP-43 aggregation causes motor deficits by activating microglia. Exercise intervention, by enhancing clusterin to block the complement pathway, prevents motor dysfunction progression in this neurodegenerative model.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- TDP-43 aggregation is linked to neurodegeneration, microglial activation, and neuronal loss.
- The precise mechanisms of microglial-induced neuronal death remain unclear.
- Understanding these pathways is crucial for developing effective interventions.
Purpose of the Study:
- To investigate the role of mutant TDP-43 in motor cortex dysfunction.
- To elucidate the molecular mechanisms underlying microglial activation and neuronal loss.
- To explore exercise as an early interventional strategy.
Main Methods:
- Generated a mouse model overexpressing mutant human TDP-43 (M337V) in the primary motor cortex.
- Utilized in vivo 2-photon imaging to observe microglial-neuronal interactions.
- Conducted proteomics studies to identify molecular pathways involved.
- Assessed the effects of treadmill exercise on motor function and molecular markers.
Main Results:
- Overexpression of mutant TDP-43 induced motor-learning deficits.
- Microglia actively approached parvalbumin interneurons, disrupting cortical excitatory-inhibitory balance.
- Proteomics indicated complement pathway activation drives microglial activity.
- Treadmill exercise prevented motor dysfunction by increasing clusterin, which blocks the complement pathway.
Conclusions:
- Identified a novel pathway where TDP-43 aggregation leads to cortical deficits via microglial activation and complement pathway involvement.
- Demonstrated that exercise can be an effective early intervention for TDP-43-related motor dysfunction.
- Provided mechanistic insights into how exercise training benefits neurodegenerative disease intervention.
