Proteomic Biomarkers for Age-Related Macular Degeneration

Abstract AMD is a complex disease and a major cause of visual loss in the elderly worldwide1,2. Deposition of debris (drusen) along Bruch's membrane in the macula is the first evidence of AMD. Advanced AMD occurs in two forms, geographic atrophyandchoroidalneovascularization(CNV). Geographic atrophy develops slowly and results in blindness when focal areas of the retinal pigment epithelium (RPE) degenerate in the macula. CNV is characterized by the growth of new blood vessels from the choriocapillaris through Bruch's membrane and the RPE, causing blindness. CNV accounts for over 80% of AMD debilitating visual loss yet only 10–15% of cases progress to CNV. Anti-vascular endothelial growth factor (VEGF) treatments can inhibit the progression of CNV1, and antioxidant vitamins and zinc can slow dry AMD progression for select individuals3. There are no universally effective therapies for the prevention of AMD, nor are there therapies to repair retinal damage in advanced AMD. However, intense AMD drug discovery efforts are ongoing4, driven by the aging population and projected increases in advanced AMD5. There is growing consensus that AMD is an inflammatory disease involving dysregulation of the complement system1,2,6. This evidence includes complement-associated AMD susceptibility genes7,8,9,10,11,12,13 and elevated complement proteins in drusen14,15,16 and AMD Bruch's membrane/choroid17. About 60% of proteins elevated in macular AMD Bruch's membrane/choroid are involved in inflammatory processes and the immune response17. For many years AMD has been hypothesized as a systemic disease15, based in part on the presence of retinal drusen in patients with membranoproliferative glomerulonephritis type II18 and more recently on systemic complement activation in the disease19. The molecular triggers of the AMD inflammatory response have yet to be well defined; however, reactive oxygen species are key regulators of inflammatory reactions and the immune response20,21,22. Oxidative stress appears to be a likely catalyst of AMD pathology as smoking significantly increases AMD risk23 and a host of oxidative modifications are elevated in AMD ocular tissues and body fluids14,24,25,26,27,28,29,30,31,32. Why retinal tissues in select individuals become more susceptible to oxidative damage in old age remains unknown. AMD susceptibility genes have been implicated in over 50% of AMD cases33, yet many individuals with AMD risk-genotypes never develop advanced AMD. Unfortunately, clinicians cannot predict which patients will progress to advanced AMD with severe visual loss, and the prevalence of advanced AMD is approaching epidemic proportions5. This chapter reviews current evidence supporting plasma protein carboxymethyllysine (CML), pentosidine and carboxyethylpyrrole (CEP) as AMD biomarkers29,30. These proteomic biomarkers in combination with genomic markers of AMD risk offer promise for enhancing clinical prognostic capability and improved monitoring of AMD therapeutics.