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Trevor McGill, Laurie Renner, Alison Weiss, Kay Rittenhouse, Justin Lee, Joachim Fruebis, Marvin Sperling, Martha Neuringer; Immunohistochemical analysis of primate drusen reveals homologous protein expression between monkey and human. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4106.
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A hallmark of age-related macular degeneration (AMD) is the accumulation of drusen under the retinal pigment epithelium (RPE); however, limited animal models are available that exhibit drusen consistent with those found in the human condition. Nonhuman primate models of dry AMD express drusen in two forms: rhesus and cynomolgus macaques commonly exhibit late onset drusen accumulation that develops over many years, whereas specific colonies of Japanese and cynomolgus macaques exhibit dominantly inherited early onset drusen accumulation that begins early in life and progresses rapidly. We examined the expression of key immunohistochemical markers of human drusen in both early and late onset primate drusen phenotypes.
Eyes from Japanese and rhesus macaques ranging from 2 to 38 years old were enucleated, hemisected, and immersion fixed in 4% paraformaldehyde overnight. Frozen OCT embedded eyes were sectioned at 14 um and collected in 5-slide series. One slide in each series was stained using cresyl violet to examine overall retinal morphology and identify sub-RPE drusen deposits. Adjacent sections were stained using antibodies against C5b9, vitronectin, clusterin, ApoE, C3, C5, membrane cofactor protein, annexin, and anti-beta-amyloid antibody clones 4G8 and 6E10.
Drusen in rhesus macaques is more centralized around the macula, whereas Japanese macaque drusen extend throughout the retina. Drusen were identified by their characteristic sub-RPE morphology in both species. Drusen accumulation increased with age in both species. Immunohistochemical staining demonstrated expression of C5b9, vitronection, clusterin, Apo-E, C5, membrane cofactor protein in drusen in both species in the most severe cases. Less severely affected animals expressed only some of the above markers. Anti-beta-amyloid (6E10) was also expressed in drusen of both species. Interestingly, anti-beta-amyloid (4G8) was expressed in photoreceptor outer segments and its expression increased with age, a result described previously in mice and humans.
Drusen in both rhesus and Japanese macaque retinas positively stain with the same immunohistochemical markers as human drusen, and in an age dependent manner. These findings suggest that both Japanese and rhesus macaques may provide useful models for examining factors involved in drusen accumulation and for testing potential AMD therapies.
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