Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model

Piroska Elizabeth Rakoczy, Dan Zhang, Terry Robertson, Nigel L. Barnett, John Papadimitriou, Ian Jeffrey Constable, Chooi May Lai

Research output: Contribution to journalArticleResearchpeer-review

125 Citations (Scopus)

Abstract

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 break-down 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.

Original languageEnglish
Pages (from-to)1515-1524
Number of pages10
JournalAmerican Journal of Pathology
Volume161
Issue number4
DOIs
Publication statusPublished - 1 Oct 2002
Externally publishedYes

Fingerprint

Macular Degeneration
Transgenic Mice
Retinal Pigments
Epithelial Cells
Geographic Atrophy
Biological Phenomena
Cathepsin D
Photoreceptor Cells
Corneal type 1 Macular dystrophy
Blindness
Transmission Electron Microscopy
Phagocytosis
Atrophy
Cell Death
Animal Models
Cell Proliferation

Cite this

Rakoczy, Piroska Elizabeth ; Zhang, Dan ; Robertson, Terry ; Barnett, Nigel L. ; Papadimitriou, John ; Constable, Ian Jeffrey ; Lai, Chooi May. / Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model. In: American Journal of Pathology. 2002 ; Vol. 161, No. 4. pp. 1515-1524.
@article{e87de469b8594ff79eec752b361bc587,
title = "Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model",
abstract = "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 break-down 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.",
author = "Rakoczy, {Piroska Elizabeth} and Dan Zhang and Terry Robertson and Barnett, {Nigel L.} and John Papadimitriou and Constable, {Ian Jeffrey} and Lai, {Chooi May}",
year = "2002",
month = "10",
day = "1",
doi = "10.1016/S0002-9440(10)64427-6",
language = "English",
volume = "161",
pages = "1515--1524",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier",
number = "4",

}

Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model. / Rakoczy, Piroska Elizabeth; Zhang, Dan; Robertson, Terry; Barnett, Nigel L.; Papadimitriou, John; Constable, Ian Jeffrey; Lai, Chooi May.

In: American Journal of Pathology, Vol. 161, No. 4, 01.10.2002, p. 1515-1524.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model

AU - Rakoczy, Piroska Elizabeth

AU - Zhang, Dan

AU - Robertson, Terry

AU - Barnett, Nigel L.

AU - Papadimitriou, John

AU - Constable, Ian Jeffrey

AU - Lai, Chooi May

PY - 2002/10/1

Y1 - 2002/10/1

N2 - 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 break-down 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.

AB - 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 break-down 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.

UR - http://www.scopus.com/inward/record.url?scp=0036790377&partnerID=8YFLogxK

U2 - 10.1016/S0002-9440(10)64427-6

DO - 10.1016/S0002-9440(10)64427-6

M3 - Article

VL - 161

SP - 1515

EP - 1524

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 4

ER -