Emerging evidence supports intricate association between Müller glial activation/ neuroinflammation and mitochondrial dysfunction as main contributors of retinal ganglion cell death in glaucoma; however, the molecular signals that connect these events are obscure. Now, reporting in this paper, Choi et al. show that apolipoprotein A-I binding protein (AIBP) may represent such a signal and play a critical role in suppressing Muller glial activation and protecting RGCs against glia-driven neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration.
Apolipoprotein A-I binding protein (AIBP) may play a critical role in suppressing Müller glial activation and protecting RGCs against glia-driven neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration.
The authors used a mouse model of acute elevation of intraocular pressure (IOP) by cannulation of the anterior chamber of the eye, as well as DBA/2J mice, which develop glaucoma in response to a spontaneous elevation of IOP. In both models, they found that elevation of IOP caused a significant decrease in AIBP levels in RGCs. Importantly, using AIBP knockout mice (Apoa1bp-/-), they showed that AIBP deficiency not only exacerbated RGC loss to elevated IOP, but naive Apoa1bp-/- mice also developed compromised visual acuity or decreased spatial frequency measured by optomotor response when compared to wild-type control mice - indicating a role for AIBP in maintaining normal visual function.
Next, the authors showed that the decrease of AIBP expression in the retinas of experimental models of glaucoma as well as in human patients was associated with increased levels of toll-like receptor-4 activation and interleukin 1β (IL-1β) production in Muller glial endfeet. These are key signals associated with activated glial cells and retinal neuroinflammation. Consistently, AIBP deficiency resulted in mitochondrial fragmentation, reduced ATP production and impaired mitochondrial dynamics in the retina. In contrast, administration of AIBP by intravitreal injection promoted RGC survival and inhibited inflammatory responses in the high IOP mouse model.
Collectively, these results suggest that elevated IOP-induced decrease of AIBP expression compromised mitochondrial network and function in RGCs and Müller glia, leading to reactive gliosis and exacerbated RGC vulnerability to cell death. Administration of recombinant AIBP prevented RGC death and inhibited inflammatory responses and cytokine production in Müller glia in vivo. Yet, we still do not know how elevated IOP signals Müller glia and RGCs to downregulate AIBP, and if AIBP expression in Müller glia and RGC contribute equally to the pathogenesis of glaucoma. In any case, these findings suggest a possibility of utilizing recombinant AIBP as a therapeutic agent for glaucoma through maintaining mitochondrial activity and function and suppressing glial activation.