Age-related Macular Degeneration

Subretinal Deposit in Mouse
Subretinal deposit in mouse retina of 6 moths old mice with altred photo-
receptor metabolism.

Age-related macular degeneration (AMD) is one of the leading causes for blindness in the industrialized world1. The disease is caused by a multitude of environmental and genetic factors with age being the biggest risk factor2-4. AMD is characterized by the formation of drusen, which are deposits of cellular debris that can vary in size, type and location1. Drusen on the basal side of the retinal-pigmented epithelium can be classified into hard or soft drusen. While hard drusen up to a certain size are part of the normal aging process and are also found in the peripheral retina5, soft drusen on the other hand are a hallmark of the disease pathology and are generally located in the macula area, the center of high acuity vision in humans. Drusen in the subretinal space are referred to as subretinal drusenoids, which have been shown to increase the risk of disease progression6,7.

As the disease advances and drusen become larger, loss of visual function occurs due to retinal-pigmented epithelium and photoreceptor atrophy (dry AMD). Extended patches of retinal-pigmented epithelium and photoreceptor loss are usually referred to as geography atrophy8. In some cases, the progression of the disease can take an alternative path resulting in neovascular invasion of the choriocapillaris across the Bruch’s membrane and retinal-pigmented epithelium into the photoreceptor layer1. Leakage from these newly formed vessels can cause subretinal hemorrhage accelerating retinal-pigmented epithelium and photoreceptor loss. This stage of the disease is commonly referred to as wet AMD. It affects roughly 15% of all AMD patients’ age 80 and older and if left untreated, it can result in complete central vision loss4. Today, wet AMD is being successfully treated with anti-angiogenic factors (anti Vascular Endothelial Growth Factor: Lucentis)2,9. In contrast, treatments for dry AMD and geographic atrophy remain exploratory2. The only treatments currently available to reduce the risk of developing advanced AMD are a combination of antioxidants and zinc10, and high dose supplementation with omega 3 fatty acids11.

Geographic Atrophy
Occurrence of Geographic Atrophy by 6 month of age with altered photo-
receptor metabolism.

How drusen develop and cause photoreceptor loss remains still unclear. It is has been proposed that with age, accumulated oxidative stress in retinal-pigmented epithelium cells affects their ability to fully digest the phagocytosed photoreceptor outer segments12-15. This would result in intracellular accumulation of only partially digested material that would then be secreted towards the basal side of the cell. Given the workload of an retinal-pigmented epithelium cell, which is to provide photoreceptors with nutrients and oxygen, recycle the visual chromophore and digest 10% of roughly 30 photoreceptor outer segments daily16-18, it is reasonable to assume that with age retinal-pigmented epithelium cells becomes less efficient. Because photoreceptor outer segments are rich in lipids19-21, cholesterol22 and proteins23, inefficiently digested outer segment could also perturb cholesterol and lipid homeostasis within the retinal-pigmented epithelium24. Such perturbations should vary regionally because of the different distribution of rods and cones and their different lipid and cholesterol contents in their outer segments. In fact, newer models seem to attribute the retinal-pigmented epithelium problem to a lipid imbalance in the retinal-pigmented epithelium itself discounting the role of photoreceptor outer segment digestion yet accounting for the high and differential lipid requirements of rods and cones22,25. We think the problem is a combination of both, where age-related metabolic changes in photoreceptors cause a lipid imbalance in the retinal-pigmented epithelium because the retinal-pigmented epithelium digests photoreceptor on a daily base. Based on that we have generated a mouse model where we perturb photoreceptor metabolism alone. Our model develops classical features of AMD including geographic atrophy.

Bibliography

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