The alternative complement pathway drives neuroinflammation and neurodegeneration in mouse models of glaucoma and optic nerve injury

Glaucoma is a leading cause of irreversible blindness worldwide, characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. Although elevated intraocular pressure (IOP) is a major risk factor, disease progression can occur despite normal IOP, highlighting the need for neuroprotective strategies beyond IOP reduction. Neuroinflammation has been implicated in glaucomatous neurodegeneration through complement system activation via the classical and lectin pathways. However, the role of the alternative pathway (AP), which functions as an amplification loop for central complement component 3 (C3) activation, in glaucoma is unclear. In this study, we investigated the role of the AP in glaucoma using a microbead-induced mouse model of glaucoma in mice deficient in either complement factor B ( Cfb −/− ), to selectively block the AP, or in C3 ( C3 −/− ) to block all three complement pathways. Our results indicate that the AP is critical for glaucoma development, and blocking this pathway resulted in significant neuroprotection, preventing loss of RGCs, axons, and visual acuity, which coincided with reduced glial activation and inflammatory signaling. Blocking the AP provided comparable neuroprotection to blocking all three complement pathways, indicating that the AP amplification loop is an essential component of destructive neuroinflammation in glaucoma. Furthermore, blocking the AP also conferred neuroprotection in the optic nerve crush model, suggesting a broader role for AP in optic neuropathies. These findings establish the AP as a key driver of complement-mediated neurodegeneration in glaucoma and highlight the therapeutic potential of targeting the AP in glaucoma and other neurodegenerative diseases. • The alternative pathway drives neurodegeneration in glaucoma. • Blocking the alternative pathway preserves RGCs, axons, and visual function in the microbead-induced mouse model of glaucoma. • Blocking the alternative pathway reduces glial activation and complement-mediated inflammation. • Blocking the alternative pathway provides neuroprotection in the optic nerve crush model. • Targeting the alternative pathway may provide a therapeutic strategy for glaucoma.