AIBP protects retinal ganglion cells against neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration
Soo-Ho Choi,
Keun-Young Kim,
Guy A. Perkins,
Sébastien Phan,
Genea Edwards,
Yining Xia,
Jungsu Kim,
Dorota Skowronska-Krawczyk,
Robert N. Weinreb,
Mark H. Ellisman,
Yury I. Miller,
Won-Kyu Ju
Affiliations
Soo-Ho Choi
Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA; Corresponding author.
Keun-Young Kim
National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, USA
Guy A. Perkins
National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, USA
Sébastien Phan
National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, USA
Genea Edwards
Hamilton Glaucoma Center and Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, 92093, USA
Yining Xia
Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
Jungsu Kim
Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
Dorota Skowronska-Krawczyk
Department of Physiology, Biophysics & Ophthalmology, University of California Irvine, Irvine, CA, 92697, USA
Robert N. Weinreb
Hamilton Glaucoma Center and Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, 92093, USA
Mark H. Ellisman
National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, USA
Yury I. Miller
Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
Won-Kyu Ju
Hamilton Glaucoma Center and Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, 92093, USA; Corresponding author.
Glaucoma is a leading cause of blindness worldwide in individuals 60 years of age and older. Despite its high prevalence, the factors contributing to glaucoma progression are currently not well characterized. Glia-driven neuroinflammation and mitochondrial dysfunction play critical roles in glaucomatous neurodegeneration. Here, we demonstrated that elevated intraocular pressure (IOP) significantly decreased apolipoprotein A-I binding protein (AIBP; gene name Apoa1bp) in retinal ganglion cells (RGCs), but resulted in upregulation of TLR4 and IL-1β expression in Müller glia endfeet. Apoa1bp−/− mice had impaired visual function and Müller glia characterized by upregulated TLR4 activity, impaired mitochondrial network and function, increased oxidative stress and induced inflammatory responses. We also found that AIBP deficiency compromised mitochondrial network and function in RGCs and exacerbated RGC vulnerability to elevated IOP. Administration of recombinant AIBP prevented RGC death and inhibited inflammatory responses and cytokine production in Müller glia in vivo. These findings indicate that AIBP protects RGCs against glia-driven neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration and suggest that recombinant AIBP may be a potential therapeutic agent for glaucoma.
