title: Local cellular sources of apolipoprotein E in the human retina and retinal pigmented epithelium: implications for the process of drusen formation.
abstract: OBJECTIVE
  The inheritance of specific apolipoprotein E allelles has been linked to atherosclerosis, Alzheimer disease, and, most recently, to the incidence of age-related macular degeneration. Apolipoprotein E is a common component of the extracellular plaques and deposits characteristic of these disorders, including drusen, which are a hallmark of age-related macular degeneration. Accordingly, we assessed the potential biosynthetic contribution of local ocular cell types to the apolipoprotein E found in drusen.
  
  
  METHODS
  We measured apolipoprotein E mRNA levels in human donor tissues using a quantitative assay of apolipoprotein E transcription, and we localized apolipoprotein E protein to specific cell types and compartments in the neural retina, retinal pigmented epithelium, and choroid using laser scanning confocal immunofluorescence microscopy.
  
  
  RESULTS
  Apolipoprotein E immunoreactivity is associated with photoreceptor outer segments, the retinal ganglion cell layer, the retinal pigmented epithelium basal cytoplasm and basal lamina, and with both collagenous layers of Bruch membrane. Apolipoprotein E appears to be a ubiquitous component of drusen, irrespective of clinical phenotype. It also accumulates in the cytoplasm of a subpopulation of retinal pigmented epithelial cells, many of which overlie or flank drusen. Mean levels of apolipoprotein E mRNA in the adult human retina are 45% and 150% of the levels measured in liver and adult brain, the two most abundant biosynthetic sources of apolipoprotein E. Apolipoprotein E mRNA levels are highest in the inner retina, and lowest in the outer retina where photoreceptors predominate. Significant levels of apolipoprotein E mRNA are also present in the retinal pigmented epithelium/choroid complex and in cultured human retinal pigmented epithelial cells.
  
  
  CONCLUSIONS
  Apolipoprotein E protein is strategically located at the same anatomic locus where drusen are situated, and the retinal pigmented epithelium is the most likely local biosynthetic source of apolipoprotein E at that location. Age-related alteration of lipoprotein biosynthesis and/or processing at the level of the retinal pigmented epithelium and/or Bruch membrane may be a significant contributing factor in drusen formation and age-related macular degeneration pathogenesis.
authors.affiliation: Center for the Study of Macular Degeneration, Neuroscience Research Institute, University of California, Santa Barbara, California 93106, USA. d_anders@lifesci.ucsb.edu
authors.forename: D H
authors.initials: DH
authors.lastname: Anderson
authors.forename: S
authors.initials: S
authors.lastname: Ozaki
authors.forename: M
authors.initials: M
authors.lastname: Nealon
authors.forename: J
authors.initials: J
authors.lastname: Neitz
authors.forename: R F
authors.initials: RF
authors.lastname: Mullins
authors.forename: G S
authors.initials: GS
authors.lastname: Hageman
authors.forename: L V
authors.initials: LV
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D016570:Bruch Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002829:Choroid / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D018613:Microscopy, Confocal; D008875:Middle Aged; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000378:metabolism*; D015593:Retinal Drusen / Q000209:etiology / Q000378:metabolism; D012374:Rod Cell Outer Segment / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D001057:Apolipoproteins E; D012333:RNA, Messenger