Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. It is characterized by the accumulation of extracellular lipid- and protein-containing deposits between the retinal pigment epithelium (RPE) and Bruch's membrane (BrM). These sub-RPE deposits may be focal (drusen) or diffuse and are likely to contribute to disease pathogenesis and progression as documented for extracellular deposits that exemplify other diseases such as Alzheimer's disease. Although the molecular bases of these diseases may be diverse, their pathogenic deposits contain many shared constituents that are attributable, in part, to local inflammation and activation of the complement cascade. The role of complement in AMD pathogenesis is supported by studies identifying complement proteins in drusen and studies implicating variations in the complement factor H (CFH) gene as the strongest genetic factor associated with AMD risk. The associated risk of CFH variants supports the hypothesis that local inflammation and activation of the complement cascade contributes to AMD pathogenesis. The repercussions of the CFH polymorphism on the entire complement system, as it pertains to the maintenance of the health of the eye, are not yet well understood and it seems likely that other triggers, modulators and/or mechanisms act in concert with CFH in disrupting the delicate equilibrium of the complement system. Prominent among these is amyloid beta (A?), a constituent of sub-RPE deposits, which is a known activator of the complement system. We hypothesize that dysregulated complement activity within the RPE/BrM/choroid contributes to RPE damage, sub-RPE deposit formation and AMD progression and A? in this region contributes to complement system dysregulation. In support of this hypothesis, we showed that A? is a viable therapeutic target in the treatment of AMD. For the present study, we have developed three novel mouse models to examine the role of complement in the development of AMD. In the first two models complement activation is suppressed or augmented, respectively, in an established AMD mouse model (Aims 1 and 2) and the third is a new humanized CFH mouse expressing either the normal or AMD risk form of CFH (Aim 3). Each model has a different capacity to accumulate activated complement components in the eye providing us a spectrum of complement deposition and complement-related phenotypes to interrogate the role of CFH in AMD.

Public Health Relevance

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the sixty- five-and-older population, and the devastating impact of its socioeconomic burden cannot be overstated. Using mouse models that faithfully recapitulate many aspects of human AMD, we have demonstrated that observed ocular defects arise from inflammation, amyloid beta (A?) deposition and complement dysregulation - mechanisms implicated in development of human AMD. Our proposed studies will further clarify the contribution of complement and A? to disease onset and progression. Validation of A? as a novel therapeutic target in AMD could lead to a fundamental paradigm shift in the understanding and treatment of AMD. Moreover, unraveling the impact of excess complement activation versus increased complement inhibition on subRPE deposit formation and RPE damage will help shape the development of complement-targeted therapies that could delay or prevent AMD.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Shen, Grace L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Medicine
United States
Zip Code
Qian, Qingwen; Mitter, Sayak K; Pay, S Louise et al. (2016) A Non-Canonical Role for ?-Secretase in the Retina. Adv Exp Med Biol 854:333-9
Ding, Jin-Dong; Kelly, Una; Landowski, Michael et al. (2015) Expression of human complement factor H prevents age-related macular degeneration-like retina damage and kidney abnormalities in aged Cfh knockout mice. Am J Pathol 185:29-42
Toomey, Christopher B; Kelly, Una; Saban, Daniel R et al. (2015) Regulation of age-related macular degeneration-like pathology by complement factor H. Proc Natl Acad Sci U S A 112:E3040-9
Mitter, Sayak K; Song, Chunjuan; Qi, Xiaoping et al. (2014) Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy 10:1989-2005
Ding, Jin-Dong; Kelly, Una; Groelle, Marybeth et al. (2014) The role of complement dysregulation in AMD mouse models. Adv Exp Med Biol 801:213-9
Bowes Rickman, Catherine; Farsiu, Sina; Toth, Cynthia A et al. (2013) Dry age-related macular degeneration: mechanisms, therapeutic targets, and imaging. Invest Ophthalmol Vis Sci 54:ORSF68-80
Cai, Jun; Qi, Xiaoping; Kociok, Norbert et al. (2012) ?-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO Mol Med 4:980-91
Ding, Jin-Dong; Johnson, Lincoln V; Herrmann, Rolf et al. (2011) Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration. Proc Natl Acad Sci U S A 108:E279-87
Liu, Yutao; Munro, Drew; Layfield, David et al. (2011) Serial analysis of gene expression (SAGE) in normal human trabecular meshwork. Mol Vis 17:885-93
Trotter, Justin H; Klein, Martin; Jinwal, Umesh K et al. (2011) ApoER2 function in the establishment and maintenance of retinal synaptic connectivity. J Neurosci 31:14413-23

Showing the most recent 10 out of 11 publications