Complement Inhibition Expands the Therapeutic Window of Amyloid-β Immunotherapy in Alzheimer's Disease

Recent advances in Alzheimer's disease immunotherapy highlight the critical importance of both active and passive immunization strategies in promoting the clearance of toxic amyloid- (A) aggregates.These immunization approaches induce the production of A-specific immunoglobulin G (IgG) antibodies, which bind to A and form immune complexes.These complexes are recognized by activating Fc gamma receptors (FcRs) on microglia, facilitating A uptake and removal.However, this beneficial clearance mechanism also triggers the complement cascade, as evidenced by upregulation of complement-related pathways.Upon FcR engagement, complement activation results in the generation of potent pro-inflammatory molecules, particularly the anaphylatoxin complement 5a (C5a).The C5a binds to its respective receptor, C5aR1, which is co-expressed with FcRs on microglia and potentially other neural cells.This interaction can lead to heightened microglial cell activation and exacerbate neuroinflammation, contributing to neuronal injury and degeneration in Alzheimer's disease.While active and passive immunotherapies are essential for clearing neurotoxic A, they may inadvertently provoke harmful inflammatory responses via the C5a-C5aR1 axis.To address this challenge, a combinatorial therapeutic strategy is recommended, which is pairing Atargeting immunotherapies with agents that block C5a-C5aR1 signaling.This integrated approach could preserve the benefits of A clearance while mitigating the risk of complement-mediated neuroinflammation, paving the way for more precise and safer immunotherapeutic interventions in Alzheimer's disease.