Aging induces cell loss and a decline in phagosome processing in the mouse retinal pigment epithelium

Age related macular degeneration (AMD) is a leading cause of irreversible vision loss. Changes in the retinal pigment epithelium (RPE) are critical to the development and progression of this disease (Ferrington et al., 2016). The RPE is a monolayer of terminally differentiated epithelial cells that play an integral part in maintaining the health of the light sensitive retinal neurons, the photoreceptors. The apical surface of the RPE interfaces with the photoreceptor outer segments, while the basal surface forms part of Bruch’s membrane, contributing to the inner most layer of the choroidal blood supply (Bok, 1993, Boulton and Dayhaw-Barker, 2001). The RPE has many functions that are essential for maintaining the normal health of the retina. It forms the outer blood-retina barrier to maintain immune privilege of the eye (Sugita, 2009), absorbs stray light to reduce oxidative stress, and maintains the health of the photoreceptors by actively removing spent photoreceptor outer segments and recycling vitamin A retinoids that are critical for light detection (Strauss, 2005). How these cells change as a function of age is critical for our understanding of age-related retinal disease, such as AMD.

Changes in the RPE with age may contribute to the progression of AMD. Previous work has shown that RPE cells lose their hexagonal shape and become larger, elongated and irregular with aging (Tarau et al., 2019). In aged human eyes, significant deterioration of the RPE layer at the macula and far peripheral retina is observed, with a reduction in RPE cell number (Rashid et al., 2016). Lipofuscin, which is an intracellular complex of waste products derived from photoreceptor outer segments, proteins and lipids, accumulates with age in the RPE (Haralampus-Grynaviski et al., 2003, Rozanowska et al., 2004). Additionally, drusen, which are extracellular waste deposits, accumulate between the RPE and Bruch’s membrane with age (Ishibashi et al., 1986). In eyes with advanced AMD, large drusen, or multiple drusen, occur alongside prominent changes in the RPE, including cell loss (Ach et al., 2015). The molecular changes in RPE cell function that contribute to lipofuscin and drusen deposition with age and in AMD are not well characterised.

Generally, it is thought that changes in how the RPE removes waste and recycles photoreceptor outer segments is crucial to the dysfunction of these cells with age and in AMD. A single RPE cell is in contact with 30-50 photoreceptors, each of which sheds about 5% of its outer segment mass daily (Zinn and Benjamin-Henkind, 1979). Hence, RPE phagocytosis is particularly important in supporting retinal health. Mechanisms involved in phagocytosis of photoreceptor outer segments involve several steps. Recognition and binding of photoreceptor outer segments in human and rodent retina involves the activation of alpha v beta 5 (αvβ5) integrin, on the apical membrane of the RPE (Finnemann et al., 1997, Nandrot et al., 2004). Binding of photoreceptor outer segments triggers the rearrangement and activation of several downstream proteins required for subsequent internalization, such as MERTK and FAK (Finnemann and Nandrot, 2006, Qin and Rodrigues, 2012). Once engulfed, photoreceptor outer segments are incorporated into phagosomes that mature as they move from the apical to basal side of RPE cells (Young and Bok, 1969). These mature phagosomes subsequently fuse with lysosomes to form phagolysosomes, prior to their degradation within the basal part of the RPE (Young and Bok, 1969). Anomalies at any step of this process could lead to downstream functional deficits in photoreceptor function, and/or accumulation of debris within the posterior eye. In humans, the phagocytic ability of RPE has been shown to decline with age, and it is significantly reduced in cultured RPE from eyes of AMD patients when compared to age-matched controls (Inana et al., 2018). Animal models that have been genetically modified to disrupt RPE phagocytosis undergo retinal degeneration and, in some cases, display accumulation of debris resembling an AMD phenotype (D'Cruz et al., 2000, Nandrot et al., 2004, Rakoczy et al., 2002). Thus, understanding how the phagocytic capacity of the RPE changes with age may be critical for identifying pathways important for the pathogenesis of AMD.

The aim of this study was to determine, in detail, the effect of aging on photoreceptor outer segment recycling in the mouse RPE, by investigating histological and molecular pathways in young and aged animals.

留言 (0)

沒有登入
gif