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

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

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10 Citations (Scopus)

Abstract

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

Original languageEnglish
JournalJCI Insight
Volume3
Issue number17
DOIs
Publication statusPublished - 2018 Sep 6
Externally publishedYes

Keywords

  • Cholesterol
  • Innate immunity
  • Ophthalmology

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Ban, N., Lee, T. J., Sene, A., Choudhary, M., Lekwuwa, M., Dong, Z., Santeford, A., Lin, J. B., Malek, G., Ory, D. S., & Apte, R. S. (2018). Impaired monocyte cholesterol clearance initiates age-related retinal degeneration and vision loss. JCI Insight, 3(17). https://doi.org/10.1172/jci.insight.120824