Age-related macular degeneration (AMD) is the most prevalent form of irreversible
blindness worldwide in the elderly population. The pathology of dry AMD consists of
macular degeneration of photoreceptors and the RPE, lipofuscin (A2E) accumulation,
and drusen formation. Mice have been widely used for generating models that simulate
human AMD features for investigating the pathogenesis, treatment and prevention of
the disease. Although the mouse has no macula, focal atrophy of photoreceptors and
RPE, lipofuscin accumulation, and increased A2E can develop in aged mouse eyes. However,
drusen are rarely seen in mice because of their simpler Bruch's membrane and different
process of lipofuscin extrusion compared with humans. Thus, analyzing basal deposits
at the ultrastructural level and understanding the ultrastructural pathologic differences
between various mouse AMD models are critical to comprehending the significance of
research findings and response to possible therapeutic options for dry AMD. Based
on the multifactorial pathogenesis of AMD, murine dry AMD models can be classified
into three groups. First, genetically engineered mice that target genes related to
juvenile macular dystrophies are the most common models, and they include abcr(-/-)
(Stargardt disease), transgenic ELOVL4 (Stargardt-3 dominant inheritary disease),
Efemp1(R345W/R345W) (Doyne honeycomb retinal dystrophy), and Timp3(S156C/S156C) (Sorsby
fundus dystrophy) mice. Other murine models target genes relevant to AMD, including
inflammatory genes such as Cfh(-/-), Ccl2(-/-), Ccr2(-/-), Cx3cr1(-/-), and Ccl2(-/-)/cx3cr1(-/-),
oxidative stress associated genes such as Sod1(-/-) and Sod2 knockdown, metabolic
pathway genes such as neprilysin(-/-) (amyloid beta), transgenic mcd/mcd (cathepsin
D), Cp(-/-)/Heph(-/Y) (ferroxidase ceruloplasmin/hepaestin, iron metabolism), and
transgenic ApoE4 on high fat and high cholesterol diet (lipid metabolism). Second,
mice have also been immunologically manipulated by immunization with carboxyethylpyrrole
(CEP), an oxidative fragment of DHA found in drusen, and found to present with dry
AMD features. Third, natural mouse strains such as arrd2/arrd2 (Mdm gene mutation)
and the senescence accelerated mice (SAM) spontaneously develop features of dry AMD
like photoreceptor atrophy and thickening of Bruch's membrane. All the aforementioned
models develop retinal lesions with various features that simulate dry AMD lesions:
focal photoreceptor degeneration, abnormal RPE with increased lipofuscin, basal infolding,
decreased melanosomes and degeneration. However, Bruch's membrane changes are less
common. Most mice develop retinal lesions at an older age (6-24 months, depending
on the models), while the Ccl2(-/-)/cx3cr1(-/-) mice develop lesions by 4-6 weeks.
Although murine models present various degrees of retinal and/or RPE degeneration,
classical drusen is extremely rare. Using electron microscopy, small drusenoid deposits
are found between RPE and Bruch's membrane in a few models including Efemp1(R345W/R345W),
Ccl2(-/-)/cx3cr1(-/-), neprilysin(-/-), transgenic mcd/mcd, and ApoE4 transgenic mice
on a high fat diet. High A2E levels are measured in the retinas of abcr(-/-), transgenic
ELOVL4, and Ccl2(-/-)/cx3cr1(-/-) mice. In summary, murine models provide useful tools
for studying AMD pathogenesis and evaluating novel therapies for this disease. This
review compares the major dry AMD murine models and discusses retinal pathology at
the ultrastructural level.
Published by Elsevier Ltd.