Impaired monocyte cholesterol clearance initiates age-related retinal degeneration and vision loss

• DOI: 10.1172/jci.insight.120824
• Publication Date: 2018-09-05T15:02:36Z
• Authors: Norimitsu Ban; Tae Jun Lee; Abdoulaye Sene; Mayur Choudhary; Michael Lekwuwa; Zhenyu Dong; Andrea Santeford; Jonathan B. Lin; Goldis Malek; Daniel S. Ory; Rajendra S. Apte
• Keywords: Drusen; Oxysterol

Advanced age-related macular degeneration (AMD), the leading cause of blindness among people over 50 years age, is characterized by atrophic neurodegeneration or pathologic angiogenesis. Early AMD extracellular cholesterol-rich deposits underneath retinal pigment epithelium (RPE) called drusen in subretinal space drusenoid (SDD) that drive disease progression. However, mechanisms and SDD biogenesis remain poorly understood. Although human abnormalities cholesterol homeostasis shares phenotypic features with atherosclerosis, it unclear whether systemic immunity local tissue metabolism regulates this homeostasis. Here, we demonstrate targeted deletion macrophage ABC transporters A1 (ABCA1) -G1 (ABCG1) leads to age-associated neurosensory retina similar seen early AMD. These mice also develop impaired dark adaptation, a cardinal feature RPE cell dysfunction patients even before central vision affected. Subretinal these progressively worsen concomitant accumulation metabolites including several oxysterols esters causing lipotoxicity manifests as photoreceptor neurodegeneration. findings suggest transport initiates key elements AMD, demonstrating importance aging promoting manifestation. Polymorphisms genes involved are associated significantly higher risk developing thus making studies translationally relevant identifying potential targets for therapy.