Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model
Open accessAbstract
Age-related macular degeneration (AMD) is the major cause of blindness in the developed world. Its pathomechanism is unknown and its late onset, complex genetics and strong environmental components have all hampered investigations. Here we demonstrate the development of an animal model for AMD that reproduces features associated with geographic atrophy; a transgenic mouse line (mcd/mcd) expressing a mutated form of cathepsin D that is enzymatically inactive thus impairing processing of phagocytosed photoreceptor outer segments in the retinal pigment epithelial (RPE) cells. Pigmentary changes indicating RPE cell atrophy and a decreased response to flash electroretinograms were observed in 11- to 12-month-old mcd/mcd mice. Histological studies showed RPE cell proliferation, photoreceptor degeneration, shortening of photoreceptor outer segments, and accumulation of immunoreactive photoreceptor breakdown products in the RPE cells. An accelerated photoreceptor cell death was detected in 12-month-old mcd/mcd mice. Transmission electron microscopy demonstrated presence of basal laminar and linear deposits that are considered to be the hallmarks of AMD. Small hard drusen associated with human age-related maculopathy were absent in the mcd/mcd mouse model at the ages analyzed. In summary, this model presents several features of AMD, thus providing a valuable tool for investigating the underlying biological processes and pathomechanism of AMD.
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The mcd/mcd transgenic mouse expresses a mutated form of cathepsin D that is enzymatically inactive.
“The importance of cathepsin D is well illustrated by the mcd/mcd transgenic mouse model which expresses a mutated form of cathepsin D rendering it enzymatically inactive (Rakoczy et al., 2002).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Rakoczy et al., 2002
mcd/mcd mice display features reminiscent of geographic atrophy in AMD, including photoreceptor cell death, diminished ERG responses, accumulation of phagocytic material in the RPE, basal laminar and linear deposits, RPE pigmentary changes, and RPE cell atrophy and proliferation.
“These mice display features reminiscent of geographic atrophy in AMD, such as photoreceptor cell death, diminished ERG responses, accumulation of phagocytic material in the RPE, basal laminar and linear deposits, RPE pigmentary changes, and RPE cell atrophy and proliferation.”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Rakoczy et al., 2002
Mouse models with disrupted RPE lysosome function show an accumulation of undegraded OS phagosomes and autophagosomes, accompanied by progressive retinal degeneration.
“Mouse models with disrupted RPE lysosome function such as those expressing a mutant form of cathepsin D (Rakoczy et al., 2002) (Section 3.7.4) or lacking the βA3/A1 crystallin (Sinha et al., 2016) show an accumulation of undegraded OS phagosomes and autophagosomes, accompanied by progressive retinal degeneration.”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Rakoczy et al., 2002
In the mutant CTSD transgenic mouse, sub-RPE deposits and photoreceptor degeneration were observed.
“In the mutant CTSD transgenic mouse, sub-RPE deposits and photoreceptor degeneration were observed (Rakoczy et al., 2002), and in a conditional Chm−/− mouse, abnormally high accumulation of lipofuscin and sub-RPE deposits were also reported (Wavre-Shapton et al., 2013).”
From Microtubule motors transport phagosomes in the RPE, and lack of KLC1 leads to AMD-like pathogenesis (2015) · cites this paper as Rakoczy et al., 2002
By 18 months of age, minimal Bruch's membrane thickening, drusen-like sub-RPE deposits, and extensive BlamD and BlinD were observed in mcd/mcd mice.
“By 18 months of age, minimal Bruch’s membrane thickening, drusen-like sub-RPE deposits, and extensive BlamD and BlinD were observed.”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Rakoczy et al., 2002
On fundoscopic exam at 9 months of age, RPE hypopigmentation, hyperpigmentation, and drusenoid lesions were present in most mcd/mcd mice, while no lesions were present in wild-type mice.
“On fundoscopic exam at 9 months of age, RPE hypopigmentation, hyperpigmentation, and drusenoid lesions were present in most mcd/mcd mice, while no lesions were present in wild-type mice.”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Rakoczy et al., 2002
ERG abnormalities (reduced a-wave and b-wave amplitudes) were present in transgenic mcd/mcd mice at 12 months of age.
“ERG abnormalities (reduced a-wave and b-wave amplitudes) were present in transgenic mcd/mcd mice at 12 months of age.”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Rakoczy et al., 2002
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References 57 · Cited by 173
Research works printed but not linked: 2
- Bressler NM, Bressler SB, Fine SL: Age-related macular degenera- tion. Surv Ophthalmol 1988, 32:375-413
- Abdelsalam A, Del Priore L, Zarbin MA: Drusen in age-related mac- ular degeneration: pathogenesis, natural course, and laser photoco- agulation-induced regression. Surv Ophthalmol 1999, 44:1-29
- Authors
- Rakoczy, P. E., Zhang, D., Robertson, T., Barnett, N. L., Papadimitriou, J., Constable, I. J., & Lai, C.-M.
- Affiliations
- The University of Western Australia (AU)
- Lions Eye Institute (AU)
- The University of Queensland (AU)
- Corresponding author
- Rakoczy, Piroska Elizabeth
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2002-10
- Volume
- 161
- Issue
- 4
- Pages
- 1515-1524
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1867306
- OpenAlex
- W1983091454
- Cited by
- 173
- References
- 57
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 3 · 2022: 3 · 2021: 8 · 2020: 9 · 2019: 1 · 2018: 3 · 2017: 7 · 2016: 3 · 2015: 10 · 2014: 8 · 2013: 9 · 2012: 5
- FWCI
- 13.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Funders
- Cardiff University
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- age-related macular degeneration, transgenic mouse model, cathepsin D, retinal pigment epithelium, photoreceptor outer segment phagocytosis, photoreceptor degeneration, photoreceptor cell death, drusen, geographic atrophy, electroretinogram, retinal aging
- MeSH terms
- Aging, Animals, Base Sequence, Cathepsin D, Disease Models, Animal, Macular Degeneration, Mice, Transgenic, Phagocytosis, Pigment Epithelium of Eye, Retina, Rod Cell Outer Segment, Time Factors, Apoptosis, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, Mice
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