The potential role of amyloid beta in the pathogenesis of age-related macular degeneration.
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.
Yoshida
Takeshi
T
Department of Ophthalmology and Visual Science and Instrumental Analysis Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
Ohno-Matsui
Kyoko
K
Ichinose
Shizuko
S
Sato
Tetsuji
T
Iwata
Nobuhisa
N
Saido
Takaomi C
TC
Hisatomi
Toshio
T
Mochizuki
Manabu
M
Morita
Ikuo
I
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000648:ultrastructure; D005136:Eye Proteins / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D015594:Optic Disk Drusen / Q000378:metabolism / Q000473:pathology; D010857:Pigment Epithelium of Eye / Q000378:metabolism* / Q000648:ultrastructure; D015843:Serpins / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D016229:Amyloid beta-Peptides; D005136:Eye Proteins; D015260:Neprilysin; D009414:Nerve Growth Factors; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C467484:VEGFA protein, human; C467480:vascular endothelial growth factor A, mouse