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

Neurobiology of disease 2025

Hoppe C, Mukai R, Refaian N, Karg M, Shirahama S, Shrestha M, Guo Y, Nwogu A, Krasniqi-Vanmeter D, Malechka VV, Ksander BR, Connor K, Gregory-Ksander M

Abstract

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 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 inflammation. 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 the 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.

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