Restoring AIBP expression in the retina provides neuroprotection in glaucoma

Abstract

Glaucoma is a neurodegenerative disease manifested in retinal ganglion cell (RGC) death and irreversible blindness. While lowering intraocular pressure (IOP) is the only proven therapeutic strategy in glaucoma, it is insufficient for preventing disease progression, thus justifying the recent focus on targeting retinal neuroinflammation and preserving RGCs. We have identified apolipoprotein A-I binding protein (AIBP) as the protein regulating several mechanisms of retinal neurodegeneration. AIBP controls excessive cholesterol accumulation via upregulating the cholesterol transporter ATP-binding cassette transporter 1 (ABCA1) and reduces inflammatory signaling via toll-like receptor 4 (TLR4) and mitochondrial dysfunction. ABCA1, TLR4 and oxidative phosphorylation components are genetically linked to primary open-angle glaucoma. Here we demonstrated that AIBP and ABCA1 expression was decreased, while TLR4, interleukin 1 beta (IL-1 beta), and the cholesterol content increased in the retina of patients with glaucoma and in mouse models of glaucoma. Restoring AIBP deficiency by a single intravitreal injection of adeno-associated virus (AAV)-AIBP protected RGCs in glaucomatous DBA/2J mice, in mice with microbead-induced chronic IOP elevation, and optic nerve crush. In addition, AIBP expression attenuated TLR4 and IL-1 beta expression, localization of TLR4 to lipid rafts, reduced cholesterol accumulation, and ameliorated visual dysfunction. These studies collectively indicate that restoring AIBP deficiency in the glaucomatous retina reduces neuroinflammation and protects RGCs and Muller glia, suggesting the therapeutic potential of AAV-AIBP in human glaucoma.

AIBP: A New Safeguard against Glaucomatous Neuroinflammation

“…Of interest, our recent and ongoing studies have revealed that deficiencies of AIBP and ABCA1, crucial regulators of cholesterol metabolism, are notably evident in RGCs and Müller glia endfeet in both glaucomatous human and mouse retinas. These results link to the degeneration of RGCs [12,13]. Importantly, these findings strongly suggest that dysregulation of cholesterol homeostasis plays a critical role in RGC degeneration and glial dysfunction in glaucomatous neuroinflammation and neurodegeneration.…”

“…Conversely, administration of recombinant AIBP prevented Müller glia-mediated inflammatory response and promoted RGC survival in a mouse model of acute IOP elevation. Intriguingly, AIBP protein expression is reduced in glaucomatous human and mouse retinas [12,13]. Based on these results, we propose that restoring AIBP expression in the retina can provide neuroprotection in glaucoma.…”

“…Remarkably, our emerging evidence demonstrated that restoring AIBP expression in the retina promotes RGC survival in experimental glaucoma [13]. In the study, we have identified AIBP as the protein regulating several mechanisms of glaucomatous neurodegeneration, including TLR4-mediated inflammatory signaling, excessive cholesterol accumulation, oxidative stress, mitochondrial dysfunction, and metabolic stress.…”

“…Given that RGCs are highly susceptible to mitochondrial stress caused by glaucomatous insults such as elevated IOP and oxidative stress [5,6,80,86,116], mitochondrial dysfunction is considered a critical causal factor in glaucomatous neuroinflammation and neurodegeneration [6,12,13]. This could be linked to mitochondrial damage-induced cellular processes, such as aging, excitotoxicity, oxidative stress, inflammasome activation, mitophagy deficiency, and sustained inflammatory response, as downstream pathological pathways contributing to the progression of glaucoma [12,13]. Thus, under glaucomatous conditions, effectively removing damaged mitochondria is an essential step for maintaining mitochondrial quality control and, consequently, protecting RGCs.…”

“…In addition to IOP elevation, accumulating evidence suggested that various mechanisms, such as oxidative stress, mitochondrial dysfunction, and inflammation, contribute to glaucomatous neurodegeneration. Furthermore, crosstalk between mitochondrial dysfunction, inflammasome activation, and inflammatory response exacerbates the progression of glaucoma [9,12,13].…”