Cognitive impairment, a common non-motor symptom of Parkinson's disease (PD), is a key factor in reducing the life quality of patients, but its pathogenesis remains unclear. Recent studies highlighted the role of Complement C3 in regulating neuroinflammation and cognitive function. This study aimed to elucidate the mechanisms through which C3 contributed to PD-related cognitive dysfunction, using a rotenone-induced mouse model. Rotenone exposure led to pronounced upregulation of astrocytic C3, while C3 deficiency significantly ameliorated neurodegeneration and α-synuclein Ser129 phosphorylation, accompanied by marked improvements in cognitive performance. Notably, the expression of C3a receptor (C3aR) was elevated in both microglia and neurons, and inhibition of C3aR with SB290157 effectively mitigated neuronal injury and cognitive decline. Mechanistically, blockade of the C3-C3aR axis suppressed microglial activation, reduced aberrant phagocytosis and synaptic engulfment, and restored synaptic plasticity. Subsequently, dark microglia characterized by activation of PKR-PERK-eIF2α-ATF4 pathways and abnormal lipid metabolism and release were also mitigated by C3 deletion or C3aR inhibition. Furthermore, inhibition of the C3-C3aR axis restored blood-brain barrier integrity, decreased TUNEL-positive cell numbers, and suppressed the expression or activation of PANoptosis-related markers in rotenone-exposed mice. In vitro experiments revealed that C3-C3aR axis promoted PANoptosome formation and PANoptosis through z-DNA and ZBP-1 interaction via mitochondrial ROS. Collectively, our findings uncovered the C3-C3aR axis as a critical mediator linking neuroinflammation, abnormal synaptic pruning, dark microglia, BBB impairments and neuron PANoptosis to cognitive decline in PD, providing new mechanistic insights and a potential therapeutic target for combating PD-related cognitive impairment.
Liu et al. (Fri,) studied this question.