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 expression 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 expression in the glaucomatous retina reduces neuroinflammation and protects RGCs and Muller glia, suggesting the therapeutic potential of AAV-AIBP in human glaucoma. Significance StatementLowering intraocular pressure is insufficient to prevent progressive neuroinflammation, retinal ganglion cell (RGC) death and vision loss in glaucoma. We show that reduced expression of AIBP is associated with increased markers of neuroinflammation, TLR4 and IL-1{beta}, in human glaucomatous retina and mouse models of glaucoma. Restoring AIBP expression by an intravitreal injection of AAV-AIBP protects RGCs and preserves visual function in mouse models of glaucoma. Mechanistically, we demonstrate that AAV-AIBP disrupts TLR4-lipid raft formation and attenuates phosphorylation of AMPK, ERK1/2 and p38 and expression of TLR4 and IL-1{beta} in vivo. Collectively, our findings suggest that AIBP-mediated disruption of retinal TLR4-lipid rafts can prevent RGC loss and demonstrate the therapeutic potential of AAV-AIBP in treatment of human glaucoma.