Work

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

Year: 2026

Type: preprint

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.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.10.758145