Complement C1q/C3-Microglia Axis in Alzheimer’s Disease: Molecular Mechanisms, Animal Evidence and Therapeutic Implications

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory decline and cognitive impairment. Synapse loss shows the stronger correlation with cognitive dysfunction than amyloid plaques or neurofibrillary tangles. In recent years, the classical complement cascade, especially the C1q and C3 components, has been viewed as a critical driver of pathological synaptic pruning mediated by microglia. Complement proteins tag synapses for developmental refinement, thereby ensuring the proper formation of neural circuits. However, in AD, abnormal reactivation of this pruning program leads to inappropriate elimination of functional synapses. Animal studies demonstrate that genetic knockout or pharmacological inhibition of complement components, including C1q, C3 and their downstream receptors (C3aR, C5aR1), preserves synaptic density and improve behavioral outcomes. These findings make complement signaling as both a mechanistic insight and a therapeutic target. This paper reviews the molecular mechanisms of the C1q/C3-microglia axis, integrates evidence from animal studies, and discusses the clinical potential of complement inhibitors such as anti-C1q antibody, C3 inhibitor and C5aR1 antagonists. This paper also mentions future clinical applications and emphasize synaptic protection as a significant therapy for AD.