Abstract
Purpose :
To ascertain significance of apolipoprotein J (APOJ) in retinal cholesterol homeostasis and function.
Methods :
In vivo imaging and quantifications of optic disc diameter along with retinal thickness by ultra-high resolution spectral domain optical coherence tomography, retinal imaging by fluorescein angiography, intraocular pressure measurements (IOP), pattern electroretinography (PERG), immuno/histochemistry, sterol quantifications, and retinal proteomics were conducted at 3, 6, and 12 months of age on wild type (WT) and Apoj-/- mice. Also, a group of Apoj-/- mice was treated for 4 months with low-dose (0.1 mg/kg) efavirenz (EFV) in drinking water and evaluated. EFV is an FDA-approved anti-HIV drug, which at low doses allosterically activates CYP46A1 involved in cholesterol elimination from the retina.
Results :
The major pathological changes in Apoj-/- vs WT mice included a statistically significant increase in the optic disc diameter (up to 45%, depending on age), a statistically significant increase in IOP (up to 3 mm Hg, depending on age), and a statistically significant decrease in PERG amplitudes (P1: up to 55% and N2: up to 59%, depending on age). Yet, the BRN3A and NeuN cell count in the retinal ganglion cell layer was unchanged, despite APOJ was immunolocalized to the nerve fiber layer and ganglion cell layer (as well as the photoreceptor outer segments and retinal pigment epithelium). In addition, there was a decrease in retinal cholesterol content due to a downregulation of retinal cholesterol biosynthesis and upregulation of retinal cholesterol metabolism. No changes in cholesterol and lipid distribution in the retina were detected, except possibly lipid accumulation in Bruch’s membrane. EFV treatment for 4 months normalized IOP and significantly improved retinal function. Additional retinal evaluations of EFV-treated mice are in progress.
Conclusions :
APOJ is important for retinal cholesterol maintenance and function. Some of the pathological consequences of APOJ absence in the eye could be rescued by CYP46A1 activation with low-dose of EFV. Supported by EY018383 and EY011373.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.