Altered High-Density Lipoprotein Expression Pattern in the Aqueous Humor From Eyes With Age-Related Macular...

Age-related macular degeneration (AMD) is associated with altered protein expression in the aqueous humor (AH). We aim to perform an unbiased proteomic analysis of the AH to identify proteomic signatures characterizing the disease's neovascular AMD (nAMD) and non-neovascular AMD (nnAMD) stages.

AH samples were collected from eyes with nAMD (n = 39), nnAMD (n = 30), and healthy control eyes (n = 36). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze the AH proteome; differentially expressed proteins underwent functional analysis. Serum high-density lipoprotein cholesterol (HDL-C) levels were correlated with AH high-density lipoprotein (HDL) pathway proteins.

Seventeen proteins were upregulated and five were downregulated in nAMD eyes compared with healthy controls. Enriched pathways include the fibrinogen complex, the complement alternate, the spherical HDL particle, and the serine protease inhibitor. Forty-six proteins were upregulated in nAMD versus nnAMD, whereas nine were downregulated. Enriched pathways included the spherical HDL particle, peptidase S1A, membrane attack complex, Sushi domain, and complement alternate pathway. No differentially expressed proteins were found between nnAMD and control eyes. Upregulated proteins associated with the spherical HDL particle pathway in nAMD, including apolipoprotein A-I, apolipoprotein A-II, and paraoxonase 1, exhibited a negative correlation with serum HDL-C levels (r = -0.43, P = 0.012; r = -0.37, P = 0.031; and r = -0.52, P = 0.002, respectively).

HDL-associated proteins exhibit increased expression in AH of nAMD eyes, independent of serum HDL-C levels. These findings suggest that serum HDL-C may not accurately reflect ocular HDL particle levels, highlighting the role of retinal lipid dysregulation in nAMD.