Cell and animal models of age‐related macular degeneration: Focus on oxidative stress and protein aggregation

Abstract

Age‐related macular degeneration (AMD) is a multifactorial disease with a long asymptomatic development period. Due to its multifactorial feature and slow development, disease modelling capturing all the elements becomes difficult if not impossible. The disease has a strong genetic background in form of certain polymorphisms in the complement system and ARMS2/HTRA1 genes providing tools for studies regarding genetics. However, AMD is much more than genetics. At least prolonged oxidative stress and subsequent protein accumulation and aggregation together with local inflammation developing to chronic in retinal pigment epithelial (RPE) cells are the key elements of the cellular pathogenesis of AMD. The RPE cells are quiescent and responsible for the wellbeing of the entire retina functioning as the link between choroidal vasculature and other layers of the retina providing necessary support for normal retinal functions. Therefore, disturbance on the cellular homeostasis of the RPE compromise the function of the entire retina. Despite being such an integral part of the retina responsible for the vision, the RPE cells withstand one the highest levels of oxidative stress throughout a lifetime of an individual. This sets certain demands for the antioxidant system's capacity to eliminate harmful oxidant molecules and prevent the spread of oxidative injury inside the cell leading to oxidative stress. However, constant oxidative challenge leads to damages on the protective system and becomes more deleterious over time. Proteins are especially prone to oxidative damage resulting increased levels of dysfunctional or aggregating proteins challenging the repair/degradative systems of the cell. Modification of oxidative status or protein degradation systems have been shown to simulate the disease state in the RPE cells and leading to a disease resembling phenotype. In vitro models are efficient tools studying certain cell specific molecular pathways such as oxidative stress, function of antioxidant defence system, and repair/degradative pathways and discovering potential druggable targets. In vivo animal models offer information how these pathways function in a native environment and how the in vitro results are translated to a functional living organism. Also, animal models offer information about the potential administration routes as well as important pharmacological data, for example. The use of most common animals in research, rodents, needs genetic engineering, for example, to achieve desired disease modelling phenotype often lacking some critical features of the disease. However, the use of these models has greatly increased the understanding of AMD pathogenesis, lead to new discoveries on disease development later confirmed in patient population, and offered new treatment strategies.