AIBP: A New Safeguard against Glaucomatous Neuroinflammation

Abstract

Glaucoma is a group of ocular diseases that cause irreversible blindness. It is characterized by multifactorial degeneration of the optic nerve axons and retinal ganglion cells (RGCs), resulting in the loss of vision. Major components of glaucoma pathogenesis include glia-driven neuroinflammation and impairment of mitochondrial dynamics and bioenergetics, leading to retinal neurodegeneration. In this review article, we summarize current evidence for the emerging role of apolipoprotein A-I binding protein (AIBP) as an important anti-inflammatory and neuroprotective factor in the retina. Due to its association with toll-like receptor 4 (TLR4), extracellular AIBP selectively removes excess cholesterol from the plasma membrane of inflammatory and activated cells. This results in the reduced expression of TLR4-associated, cholesterol-rich lipid rafts and the inhibition of downstream inflammatory signaling. Intracellular AIBP is localized to mitochondria and modulates mitophagy through the ubiquitination of mitofusins 1 and 2. Importantly, elevated intraocular pressure induces AIBP deficiency in mouse models and in human glaucomatous retina. AIBP deficiency leads to the activation of TLR4 in Müller glia, triggering mitochondrial dysfunction in both RGCs and Müller glia, and compromising visual function in a mouse model. Conversely, restoring AIBP expression in the retina reduces neuroinflammation, prevents RGCs death, and protects visual function. These results provide new insight into the mechanism of AIBP function in the retina and suggest a therapeutic potential for restoring retinal AIBP expression in the treatment of glaucoma.

Keywords: AAV; AIBP; TLR4; cholesterol; gene therapy; glaucoma; lipid rafts; mitochondria; neuroinflammation.

Figure 1

AIBP-mediated cholesterol efflux in glaucoma. Schematic overview of AIBP-associated protective effect on glia-driven neuroinflammation in glaucomatous retina. (A) Increased cholesterol accumulation by reducing AIBP and ABCA1 expression leads to TLR4-lipid raft clustering, TLR4 dimerization, TLR4-dependent inflammatory signaling, mitochondrial dysfunction, and cytokine production, resulting in sustained glia-driven neuroinflammation and RGC loss in glaucomatous retina. (B) Enhanced cholesterol efflux by AIBP to HDL or lipid-free APOA1 from TLR4-associated lipid rafts in activated glial cells reduces cholesterol accumulation and the ensuing inhibition of TLR4-dependent inflammation. This results in the inhibition of glia-driven neuroinflammation and protects RGC against cell death in the retina.

Figure 2

Mitochondrial AIBP in glaucoma. The role of mitochondrial AIBP in glaucoma. Impairment of mitochondrial function and defective mitophagy in Apoa1bp^−/− retina may contribute to glial cell activation via mitochondrial DAMPs (mtDAMPs) that are released from apoptotic cells in glaucoma.

Figure 3

The NAXE-associated NAD(P)HX repair system. The NAD(P)HX repair system. Nicotinamide adenine dinucleotide (NAD⁺, oxidized form: NADH) and Nicotinamide adenine dinucleotide phosphate (NADP⁺, oxidized form: NADPH) are hydrated by the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) or spontaneously to form R- and S-epimers. The R-form of NAD(P)HX is converted into the S-form of NAD(P)HX by AIBP (NAXE) and the S-form is then catalyzed by the ATP-dependent dehydratase. AIBP deficiency leads to the accumulation of cyclic NAD(P)HX, a toxic inhibitor of cellular NADH dehydrogenases, in an irreversible path, which in turn decreases the activity of mitochondrial OXPHOS complex I (C-I) and pyruvate dehydrogenase complex (PDHc).