The potential role of amyloid beta in the pathogenesis of age-related macular degeneration

J Clin Invest. 2005 Oct;115(10):2793-800. doi: 10.1172/JCI24635. Epub 2005 Sep 15.


Drusen are extracellular deposits that lie beneath the retinal pigment epithelium (RPE) and are the earliest signs of age-related macular degeneration (AMD). Recent proteome analysis demonstrated that amyloid beta (Abeta) deposition was specific to drusen from eyes with AMD. To work toward a molecular understanding of the development of AMD from drusen, we investigated the effect of Abeta on cultured human RPE cells as well as ocular findings in neprilysin gene-disrupted mice, which leads to an increased deposition Abeta. The results showed that Abeta treatment induced a marked increase in VEGF as well as a marked decrease in pigment epithelium-derived factor (PEDF). Conditioned media from Abeta-exposed RPE cells caused a dramatic increase in tubular formation by human umbilical vein endothelial cells. Light microscopy of senescent neprilysin gene-disrupted mice showed an increased number of degenerated RPE cells with vacuoles. Electron microscopy revealed basal laminar and linear deposits beneath the RPE layer, but we did not observe choroidal neovascularization (CNV). The present study demonstrates that Abeta accumulation affects the balance between VEGF and PEDF in the RPE, and an accumulation of Abeta reproduces features characteristic of human AMD, such as RPE atrophy and basal deposit formation. Some other factors, such as breakdown of integrity of Bruch membrane, might be necessary to induce CNV of AMD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Cells, Cultured
  • Epithelial Cells / metabolism
  • Epithelial Cells / ultrastructure
  • Eye Proteins / metabolism
  • Fetal Blood / cytology
  • Fetal Blood / metabolism
  • Humans
  • Macular Degeneration / metabolism*
  • Macular Degeneration / pathology
  • Mice
  • Mice, Knockout
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neprilysin / genetics
  • Neprilysin / metabolism
  • Nerve Growth Factors / metabolism
  • Optic Disk Drusen / metabolism
  • Optic Disk Drusen / pathology
  • Pigment Epithelium of Eye / metabolism*
  • Pigment Epithelium of Eye / ultrastructure
  • Serpins / metabolism
  • Vacuoles / metabolism
  • Vacuoles / ultrastructure
  • Vascular Endothelial Growth Factor A / metabolism


  • Amyloid beta-Peptides
  • Eye Proteins
  • Nerve Growth Factors
  • Serpins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • pigment epithelium-derived factor
  • vascular endothelial growth factor A, mouse
  • Neprilysin