**1. Introduction**

Macular degeneration refers as a progressive condition in which patients are suffering of a disease that is a leading cause of blindness in the elderly worldwide. In particular age-related macular degeneration (AMD) is characterized by two forms, wet and dry, that are classified on the presence or absence of new blood vessels (CNV) [1]. However, there is emerging evidence that significantly overlap which exists in the underlying pathogenetic mechanisms of these clinical conditions. Clarification of the overlapping process that lead to wet and dry diseases will be crucial for the future development in the prevention and treatment of AMD.

By definition, early AMD is characterized by confluent regions of drusen, which are multicomponent, heterogeneous aggregates that lie both external and internal to the retinal pigment epithelium (RPE) cells [2–3]. They are located primarily at the macular region of the retina with relative sparing of the surrounding peripheral retina.

A slow growth of drusen occurs over years or decades with RPE cell death and synaptic dysfunction during the advanced stage of AMD, with the development of advanced AMD (CNV or geographic atrophy (GA)) [4]. All we know about pathogenetic mechanism underlying AMD is that it has the RPE as the fulcrum of AMD pathogenesis. However, whereas, the stepwise development of certain maladies is relatively well-defined, no such hallmarks of disease progression have been identified in AMD.

#### **2. The RPE: at the core of AMD disease**

The RPE is the fulcrum of AMD pathogenesis. In general, in spite of interindividual heterogeneity, RPE dysfunction and atrophy precedes the final stages of AMD [5–6]. The RPE cells integrate numerous stimuli to regulate its own health, while also receiving and broadcasting signals to and from the retinal microenvironment. There are several human AMD samples displaying significant interindividual variation in RPE transcript expression, which supports the concept that heterogenic stress responses underlie a categorical AMD phenotype. The effect of specific AMD-associated stresses and AMD in retinal molecular composition have been cataloged by mean genome-wide stress-response transcriptome and proteome assays on whole-genome RPE gene. Such studies reveal common protective and deleterious RPE gene responses that could clarify the key molecular basis of the disease. One of the most important evidences involved in the AMD pathology is the crosstalk of RPE with immune and vascular system. Indeed there are numerous overlapping proangiogenic mechanisms that underlie AMD, many of which involve

the intersection of immune and vascular system. Whether this immunovascular axis modulates RPE cell is not clear. However in the presence of the AMD pathogenesis, the critical event from which there is not return is RPE dysfunction and damage, although perturbations in other tissues (e.g., choroid, Bruch's membrane, and photoreceptors) are important burdens [7–9].
