The potential role of amyloid in the pathogenesis of age-related macular degeneration
Open accessAbstract
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.
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In 27 month-old Neprilysin−/− mice, the RPE developed vacuolization, loss of tight and adherence junctions, prominent basal infoldings, and subretinal accumulation of amorphous deposits and photoreceptor outer segments, implying RPE dysfunction.
“In 27 month-old Neprilysin−/− mice, the RPE developed vacuolization, loss of the tight and adherence junctions, prominent basal infoldings, and subretinal accumulation of amorphous deposits and photoreceptor outer segments, implying RPE dysfunction.”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Yoshida et al., 2005
Neprilysin−/− mice have enhanced VEGF expression and diminished PEDF expression with no evidence of CNV or leakage on fluorescein angiography.
“The Neprilysin−/− mice have enhanced VEGF expression and diminished PEDF expression with no evidence of CNV or leakage on fluorescein angiography (Yoshida et al., 2005).”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Yoshida et al., 2005
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References 70 · Cited by 202
Research works printed but not linked: 3
- J.W. Berger, S.L. Fine, and M.G. Maguire, editors. Mosby. St. Louis, Missouri, USA. 81-154.
- Hogan, M.J., Alvarado, J.A., and Weddell, J.E. 1971. Retina. In Histology of the human eye. W.B. Saunders. Philadelphia, Pennsylvania, USA. 393-522.
- Marmor, M.F. 1998. Structure, function, and disease of the retinal pigment epithelium. In The retinal pigment epithelium. M.F. Marmor and T.J. Wolfensberger, editors. Oxford University Press. New York, New York, USA. 3-12.
- Authors
- Yoshida, T.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Corresponding author
- Yoshida, T.
- ORCID
- Yoshida, T.
- Venue
- Journal of Clinical Investigation
- Published
- 2005-10-01
- Volume
- 115
- Issue
- 10
- Pages
- 2793-2800
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1201663
- OpenAlex
- W2122106651
- Cited by
- 202
- References
- 70
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 8 · 2023: 4 · 2022: 9 · 2021: 14 · 2020: 6 · 2019: 7 · 2018: 12 · 2017: 9 · 2016: 11 · 2015: 13 · 2014: 12 · 2013: 11 · 2012: 15
- FWCI
- 8.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tokyo Medical and Dental University
- Japan Society for the Promotion of Science (16390495, 14370555, 17025046, 16390537, 14657483, 15390558)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- age-related macular degeneration, amyloid-beta, drusen, retinal pigment epithelium, neprilysin, vascular endothelial growth factor, pigment epithelium-derived factor, choroidal neovascularization, retinal pigment epithelium atrophy, Bruch's membrane, endothelial tube formation
- MeSH terms
- Pigment Epithelium-Derived Factor, Animals, Cells, Cultured, Epithelial Cells, Eye Proteins, Fetal Blood, Humans, Macular Degeneration, Neovascularization, Pathologic, Nerve Growth Factors, Pigment Epithelium of Eye, Vacuoles, Neprilysin, Optic Disk Drusen, Serpins, Amyloid beta-Peptides, Mice, Knockout, Vascular Endothelial Growth Factor A, Mice
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