The study investigates the role of complement and microglia in early synapse loss in Alzheimer's disease (AD) mouse models. Key findings include: 1. **C1q Increase and Synapse Loss**: C1q, the initiating protein of the classical complement cascade, is upregulated and associated with synapses before the onset of overt plaque deposition in AD mouse models. Inhibition of C1q, C3, or the microglial complement receptor CR3 reduces synapse loss and the number of phagocytic microglia. 2. **Toxic Effects of Aβ Oligomers**: C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation (LTP). 3. **Microglial Phagocytic Activity**: Adult microglia in the brain engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. These findings suggest that the complement-dependent pathway and microglia, which prune excess synapses during development, are inappropriately activated in AD, leading to synapse loss. The study provides new insights into the early mechanisms of synapse loss in AD and highlights potential therapeutic targets for AD and other neurodegenerative diseases involving synaptic dysfunction.The study investigates the role of complement and microglia in early synapse loss in Alzheimer's disease (AD) mouse models. Key findings include: 1. **C1q Increase and Synapse Loss**: C1q, the initiating protein of the classical complement cascade, is upregulated and associated with synapses before the onset of overt plaque deposition in AD mouse models. Inhibition of C1q, C3, or the microglial complement receptor CR3 reduces synapse loss and the number of phagocytic microglia. 2. **Toxic Effects of Aβ Oligomers**: C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation (LTP). 3. **Microglial Phagocytic Activity**: Adult microglia in the brain engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. These findings suggest that the complement-dependent pathway and microglia, which prune excess synapses during development, are inappropriately activated in AD, leading to synapse loss. The study provides new insights into the early mechanisms of synapse loss in AD and highlights potential therapeutic targets for AD and other neurodegenerative diseases involving synaptic dysfunction.