Biomarkers of lipid status and metabolism in retinal ageing – BLISAR

Age-related macular degeneration (AMD) is responsible for 50 % of the cases of blindness in industrialized countries. It results from a pathological ageing of the retina, linked to a dysfunction of the retinal pigment epithelium (RPE), responsible for the recycling of the photoreceptors outer segments and for the nutritional exchanges with the blood circulation, through the vascular choroid (CH). Current treatments are limited to the neovascular form of the disease, and cannot always avoid severe visual loss. Thus, preventive strategies aiming at the reduction of the incidence of AMD are still of major public health importance, as they may reduce the costs associated to the treatment of neovascular AMD, but also to the loss in autonomy and quality of life associated with AMD-related visual impairment.

N-3 polyunsaturated fatty acids (PUFA) and cholesterol metabolisms are highly suspected to play a role in AMD pathophysiology. Indeed, epidemiological studies have very consistently shown a 40% reduction in risk for AMD in subjects with high dietary intake of n-3 PUFA, and in particular long-chain n-3 PUFA docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). In order to better understand the role of n-3 PUFA in retinal ageing, there is a need to identify reliable circulating biomarkers of n-3 PUFA retinal status. In an innovative approach using comprehensive lipidomics in a preliminary post-mortem study, we recently developed and identified several good candidates to be circulating biomarkers of n-3 PUFA retinal status. Whether these circulating biomarkers of lipid status may be associated with AMD remains to be determined.

Besides, impairment of cholesterol metabolism in AMD was suggested by histological, experimental and genetic studies. HDL and LDL lipoproteins are carriers of n-3 PUFA to the retina. CETP (cholesterol ester transfer protein) and LCAT (lecithin-cholesterol acyltransferase) are key proteins in the remodeling of cholesteryl esters (CE) in lipoproteins. Among others, a gene polymorphism in CETP was associated with the risk of AMD. The results of our previous post-mortem study also suggested that the ratio of the DHA concentration in plasma CE to the DHA concentration in plasma phosphatidylcholines (PC) may represent a biomarker of the concentration of DHA in the RPE/CH. This ratio can be considered as an indirect indicator of the LCAT enzyme activity, which is responsible for the plasma CE synthesis in HDL. All these data comfort the implication of cholesterol metabolism in the transfer of n-3 PUFA to the retina.

The objective of the proposal is to overcome two challenges:
- A scientific one, to better understand the role of n-3 PUFA, cholesterol metabolism, and their interaction in AMD.
- A technological one, to identify and validate new biomarkers of lipid status with high discriminative value for AMD.

The multidisciplinary project will combine a case-control study of AMD, allowing the identification of biomarkers associated with AMD and two post-mortem studies allowing the study of the associations of these biomarkers with ocular n-3 PUFA status (retina, RPE/CH), firstly in elderly donors without AMD and secondly in eyes from donors affected by AMD. It represents a first step towards the design of a large scale interventional study, aiming at the reduction of the incidence of AMD with supplementation in n-3 PUFA.
By studying a major aspect of retinal ageing, which has considerable repercussions on the wellbeing and autonomy of elderly subjects, the present project perfectly fits in the “health and wellbeing” challenge (3.4), and particularly of subtheme 12 “Normal and pathological ageing, autonomy and quality of life”.