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The retinal pigmented epithelium (RPE) forms the outer blood-retinal barrier, provides nutrients, recycles visual pigment, and removes spent discs from the photoreceptors, among many other functions. Because of these critical roles in visual homeostasis, the RPE is a principal location of disease-associated changes in age-related macular degeneration (AMD), emphasizing its importance for study in both visual health and disease. Unfortunately, there are no early indicators of AMD or disease progression, a void that could be filled by the development of early AMD biomarkers. Exosomes are lipid bilayer membrane vesicles of nanoscale sizes that are released in a controlled fashion by cells and carry out a number of extra- and intercellular activities. In the RPE they are released from both the apical and basal sides, and each source has a unique signature/content. Exosomes released from the basolateral side of RPE cells enter the systemic circulation via the choroid and thus represent a potential source of retinal disease biomarkers in blood. Here we discuss the potential of targeted immunocapture of eye-derived exosomes and other small extracellular vesicles from blood for eye disease biomarker discovery.

The retinal pigmented epithelium (RPE) forms the outer blood-retinal barrier and provides nutrients and recycling of visual pigment to the photoreceptors, among many other functions. The RPE is also a key site of pathophysiological changes in age-related macular degeneration, making it an important focus of study in both visual health and disease. Exosomes are nanometer-sized vesicles that are released by cells in a controlled fashion and mediate a range of extra- and intercellular activities. Some key exosome actions include cell-cell communication, immune modulation, extracellular matrix turnover, stem cell division/differentiation, neovascularization, and cellular waste removal. While much is known about their role in cancer and cardiovascular disease, exosome function in the many specialized tissues of the eye is just beginning to undergo rigorous study. Here we review current knowledge of the functions and roles of exosomes and other small extracellular vesicles released from the RPE. In particular, we discuss the potential role and importance of polarized exosome release from the RPE.

It has long been established that β-Secretase (BACE) plays a critical role in the formation of amyloid plaques in Alzheimer's Disease patients, but it is only recently that the importance of β-secretases in retinal pathophysiology has been recognized. BACE expression is elevated in response to stress, and downregulation results in lysosomal abnormalities and mitochondrial changes. Inhibition of BACE can lead to reduced retinal function, retinal thinning, lipofuscin accumulation and vascular dysfunction in mice. Furthermore, BACE inhibition accelerates choroidal neovascularization (CNV) in mice. We propose that BACE plays an important role in retinal homeostasis and that BACE upregulation in response to stress is a protective measure.

Variations in several complement genes are now known to be significant risk factors for the development of age-related macular degeneration (AMD). Despite dramatic effects on disease susceptibility, the underlying mechanisms by which common polymorphisms in complement proteins alter disease risk have remained unclear. Genetically modified mice in which the activity of the complement has been altered are available and can be used to investigate the role of complement in the pathogenesis of AMD. In this mini review, we will discuss some existing complement models of AMD and our efforts to develop and characterize the ocular phenotype in a variety of mice in which complement is either chronically activated or inhibited. A spectrum of complement dysregulation was modeled on the APOE4 AMD mouse model by crossing these mice to complement factor H knockout (cfh-/-) mice to test the impact of excess complement activation, and by crossing them to soluble-complement-receptor-1-related protein y (sCrry) mice, in which sCrry acts as a potent inhibitor of mouse complement acting in a manner similar to CFH. In addition, we have also generated humanized CFH mice expressing normal and risk variants of CFH.