APOB100 transgenic mice exemplify how the systemic circulation content may affect the retina without altering retinal cholesterol input.

Apolipoprotein B (APOB) is a constituent of unique lipoprotein particles (LPPs) produced in the retinal pigment epithelium (RPE), which separates the neural retina from Bruch's membrane (BrM) and choroidal circulation. These LPPs accumulate with age in BrM and contribute to the development of age-related macular degeneration, a major blinding disease. The APOB100 transgenic expression in mice, which unlike humans lack the full-length APOB100, leads to lipid deposits in BrM. Herein, we further characterized APOB100 transgenic mice. We imaged mouse retina in vivo and assessed chorioretinal lipid distribution, retinal sterol levels, retinal cholesterol input, and serum content as well as tracked indocyanine green-bound LPPs in mouse plasma and retina after an intraperitoneal injection. Retinal function and differentially expressed proteins were also investigated. APOB100 transgenic mice had increased serum LDL content and an additional higher density HDL subpopulation; their retinal cholesterol levels (initially decreased) became normal with age. The LPP cycling between the RPE and choroidal circulation was increased. Yet, LPP trafficking from the RPE to the neural retina was limited, and total retinal cholesterol input did not change. There were lipid deposits in the RPE and BrM, and retinal function was impaired. Retinal proteomics provided mechanistic insights. Collectively, our data suggested that the serum LDL/HDL ratio may not affect retinal pathways of cholesterol input as serum LPP load is mainly handled by the RPE, which offloads LPP excess to the choroidal circulation rather than neural retina. Different HDL subpopulations should be considered in studies linking serum LPPs and age-related macular degeneration.