ScholarWorks@경상국립대학교

초록

Glaucoma is a neurodegenerative disease manifested by retinal ganglion cell (RGC) death and irreversible blindness. We have identified apolipoprotein A-I binding protein (AIBP) that controls excessive cholesterol accumulation and neuroinflammation in the retina by upregulating the cholesterol transporter ABCA1 and reducing TLR4 signaling and mitochondrial dysfunction. Here, we demonstrated that AIBP and ABCA1 expression were decreased, whereas Toll-like receptor 4 (TLR4), interleukin-1β (IL-1β), and the cholesterol content increased in the retina of patients with glaucoma and mouse models of glaucoma. Restoring AIBP deficiency by a single intravitreal injection of adeno-associated virus (AAV) protected RGCs and ameliorated visual dysfunction in experimental glaucoma. Conversely, AAV-mediated RGC-specific AIBP knockdown exacerbated RGC loss and visual dysfunction in a mouse model of glaucoma. Mechanistically, AAV-AIBP attenuated TLR4 and IL-1β expression and localization of TLR4 to lipid rafts, reduced cholesterol accumulation, and ameliorated visual dysfunction. Additionally, AAV-AIBP promoted mitochondrial complexity and function in Müller glia in vivo. Recombinant AIBP protein inhibited TLR4 and IL-1β activation and alleviated mitochondrial dysfunction in Müller glia in response to elevated pressure in vitro. These studies indicate that restoring AIBP expression in the glaucomatous retina reduces neuroinflammation and protects RGCs and Müller glia, suggesting the therapeutic potential of AAV-AIBP in human glaucoma. © 2025 The American Society of Gene and Cell Therapy

키워드