Restoring AIBP expression in the retina provides neuroprotection in glaucoma.

Journal: Molecular therapy : the journal of the American Society of Gene Therapy
Published Date: May 9, 2025

Abstract

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, while TLR4, 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 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.

Authors

  • Won-Kyu Ju
    Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA 92039, USA. Electronic address: wju@health.ucsd.edu.
  • Keun-Young Kim
    National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA 92039, USA.
  • Tonking Bastola
    Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA 92039, USA.
  • Ziyao Shen
    Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA 92039, USA.
  • Seunghwan Choi
    Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA 92039, USA.
  • Guy A Perkins
    National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA 92039, USA.
  • Sinwoo Hwang
    Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA 92039, USA.
  • Jungsu Kim
    Department of Medicine, University of California San Diego, La Jolla, CA 92039, USA.
  • Jin-Woo Kwon
    Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA 92039, USA; Department of Ophthalmology and Visual Science, St. Vincent's Hospital, The Catholic University of Korea, Jungbu-daero 93, Paldal-gu, Suwon, Gyeonggi-do, 16247, Republic of Korea.
  • Muna Poudel
    Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA 92039, USA.
  • Sébastien Phan
    National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA 92039, USA.
  • Fan Xia
  • Shuizhen Shi
    Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, TX, 77555-0144, USA.
  • Hyunkyung Cho
    Hamilton Glaucoma Center, and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA 92039, USA; Department of Ophthalmology, Gyeongsang National University Changwon Hospital, Gyeongsang National University, School of Medicine, Changwon, Gyeongsangnam-do, 51472, Republic of Korea.
  • Hua Liu
    Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, TX, 77555-0144, USA.
  • Wenbo Zhang
    Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, TX, 77555-0144, USA.
  • Robert N Weinreb
    Hamilton Glaucoma Center, Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, California.
  • Mark H Ellisman
    National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA 92039, USA.
  • Yury I Miller
    Department of Ophthalmology and Visual Science, St. Vincent's Hospital, The Catholic University of Korea, Jungbu-daero 93, Paldal-gu, Suwon, Gyeonggi-do, 16247, Republic of Korea; Raft Pharmaceuticals LLC, San Diego, CA 92121, USA.
  • Soo-Ho Choi
    Department of Ophthalmology and Visual Science, St. Vincent's Hospital, The Catholic University of Korea, Jungbu-daero 93, Paldal-gu, Suwon, Gyeonggi-do, 16247, Republic of Korea. Electronic address: soc002@health.ucsd.edu.

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