Abstract
Purpose: :
Increasing evidence indicates a link between cholesterol and age- related macular degeneration. Cholesterol is eliminated from different organs by lipoprotein- and enzyme-mediated mechanisms. In the retina, cytochrome P450 CYP27A1 (CYP27A1) was shown to be important for enzyme-dependent cholesterol elimination. Deficiency of CYP27A1 in humans leads to a lipid storage disease called cerebrotendinous xanthomatosis, hallmarked by premature atherosclerosis, neurodegeneration, juvenile cataracts, and early retinal senescence. The purpose of this work is to evaluate the effects of CYP27A1 deficiency on visual function in mice.
Methods: :
We utilize high-resolution spectral-domain optical coherence tomography (OCT) and fluorescein angiography for evaluation of retinal morphology, and electroretinography (ERG) to assess visual function.
Results: :
At the age of 1.5 months, CYP27A1 KO males begin to develop bilateral retinal deposits in the inferior retina as revealed by OCT. By the age of 12-months, some of the male KOs exhibit retinal pathology both in the inferior retina and near the optic nerve. The pathology starts from the choroid and penetrates through Bruch’s membrane and RPE into the inner retina. Doppler flow OCT reveals impaired blood flow in CYP27A1 KOs and fluorescein angiography shows blood leakage in the area of pathology. We observe statistically significant increases in the amplitude of the photopic b-wave in 3 month CYP27A1 female KOs as compared to WT littermates by ERG. Male CYP27A1 KOs also have statistically significant increases in the photopic b-wave amplitude, but starting later, at 6 months.
Conclusions: :
Disruption of CYP27A1-mediated cholesterol elimination has significant effects on retinal structure and function. Investigation of whether CYP27A1 deficiency leads to inflammation and neovascularization is underway.
Keywords: retina • age-related macular degeneration • enzymes/enzyme inhibitors