Downregulation of astrocytic C3 production alleviates neuronal mitochondrial dysfunction in tauopathy models
Astrocytic complement system over-activation is linked to the progression of neuronal dysfunction and degeneration in neurodegenerative disorders such as Alzheimer's Disease (AD) and tauopathies. Blocking Complement C3 (C3) expression rescues neuronal dysfunction and loss in tauopathy models, however, mechanism of C3 mediating neurodegeneration remains unclear. In this study, we found that activated astrocytes can trigger tau-mediated neuronal mitochondrial swelling and dysfunction through C3 over-production. Increased neuronal mitochondrial dysfunction resulted in the activation of the necroptosis pathway. Our data revealed that downregulation of astrocytic C3 production by anserine, a natural imidazole dipeptide that can target astrocytes had the ability to prevent neuronal mitochondrial dysfunction and necroptosis activation, both in the in vitro and in vivo tauopathy models. Suppression of astrocyte activation and C3 production also rescued the cognitive function and prolonged the survival rate. Our findings reveal the neurotoxic role of astrocytic C3 in mediating neuronal mitochondrial dysfunction and sequent death through promoting tau pathology and suggest the therapies that can downregulate A1 astrocyte activation and C3 secretion such as anserine have a potential role in alleviating this neurotoxic effect.