Therapeutic AIBP expression contributes to synaptic preservation and vision restoration against glaucomatous neuroinflammation

Abstract Lowering intraocular pressure (IOP) is the only approved treatment for glaucoma, yet retinal ganglion cell (RGC) degeneration and vision loss often progress despite reducing IOP. Apolipoprotein A-I binding protein (AIBP) stabilizes ATP-binding cassette subfamily A member 1 (ABCA1) and promotes cholesterol efflux, thus controlling cholesterol-rich lipid rafts and restraining lipid raft-dependent Toll-like receptor 4 (TLR4) inflammatory signaling. Here we show that AAV2-mediated expression of human AIBP (hAIBP) preserves inner retinal synaptic integrity and visual function in experimental glaucoma without altering IOP. In DBA/2J mice, a single intravitreal injection of AAV2-hAIBP at 5 months protected RGCs and preserved pattern electroretinogram and pattern visual evoked potential responses at 10 months, even though IOP was indistinguishable from empty-vector controls. AAV2-hAIBP preserved CaMKII and synapsin phosphorylation, restored synaptophysin and PSD95 in the inner plexiform layer, and reduced the expression of TLR4, complement C1q, IBA1, IL-1β, and IL-6 induction in Müller glia and microglia. Comparable protection was observed in microbead-induced ocular hypertension in C57BL/6 mice, both when the AAV2-hAIBP was delivered before microbead injection and when it was delivered after IOP elevation was established. Elevated IOP reduced endogenous retinal AIBP and ABCA1 expression, and AAV2-hAIBP restored both. Protection required the TLR4-binding domain, as an AIBP mutant lacking this domain failed to preserve RGCs. Conversely, Apoa1bp −/− retinas exhibited increased CaMKII phosphorylation and reduced synaptophysin in the absence of elevated IOP. These findings identify synaptic preservation through the AIBP–TLR4 axis as an IOP-independent therapeutic mechanism and support AAV2-hAIBP as a candidate gene therapy for glaucoma. Graphic Abstract AAV2-hAIBP expression protects RGCs and preserves visual function in chronic DBA/2J (therapeutic mode) and microbead-induced ocular hypertension (preventive and therapeutic modes) without lowering IOP. Retinal hAIBP expression promotes ABCA1-dependent cholesterol efflux, limits lipid raft–dependent TLR4 signaling, keeps Müller glia and microglia quiescent, and reduces C1q, IL-1β, and IL-6. In the IPL, retinal hAIBP expression normalizes CaMKII and synapsin phosphorylation and restores synaptophysin and PSD95. Protection requires the TLR4-binding domain, and Apoa1bp −/− retinas show synaptic impairment without elevated IOP.