Role In Pathogenesis Of Age-related Macular Degeneration Research Articles

The molecular genetic basis of age-related macular degeneration: an overview

Age-related macular degeneration (AMD) is a complex disorder of the eye and the third leading cause of blindness worldwide. With a multifactorial etiology, AMD results in progressive loss of central vision affecting the macular region of the eye in elderly. While the prevalence is relatively higher in the Caucasian populations, it has gradually become a major public health issue among the non-Caucasian populations (including Indians) as well due to senescence, rapidly changing demographics and life-style factors. Recent genome-wide association studies (GWAS) on large case-control cohorts have helped in mapping genes in the complement cascade that are involved in the regulation of innate immunity with AMD susceptibility. Genes involved with mitochondrial oxidative stress and extracellular matrix regulation also play a role in AMD pathogenesis. Majority of the associations observed in complement (CFH, CFB, C2 and C3) and other (ARMS2 and HTRA1) genes have been replicated in diverse populations worldwide. Gene-gene (CFH with ARMS2 and HTRA1) interactions and correlations with environmental traits (smoking and body mass index) have been established as significant covariates in AMD pathology. In this review, we have provided an overview on the underlying molecular genetic mechanisms in AMD worldwide and highlight the AMD-associated-candidate genes and their potential role in disease pathogenesis.

Immunological protein expression profile in Ccl2/Cx3cr1 deficient mice with lesions similar to age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the United States. Ccl2 knock-out (KO) mice sporadically develop the cardinal features of AMD in their senescent stage. Humans bearing a loss of function variant or single nucleotide polymorphism (SNP) in CX3CR1 are at increased risk of developing AMD. We recently developed Ccl2−/−/Cx3cr1−/− mice, which consistently develop retinal degeneration with many AMD features. Since there is strong evidence for an immunological role in AMD pathogenesis, we examined ocular immune protein expression levels in Ccl2−/−/Cx3cr1−/−, Ccl2−/−, Cx3cr1−/−, and age-matched wild-type (WT) mice. Immunohistochemistry revealed increased complement C3d in Bruch's membrane, retinal pigment epithelium (RPE), choroidal capillaries, and particularly drusen of the Ccl2−/−/Cx3cr1−/− mice relative to the WT controls. No change was detected in single KO mice. Real-time RT-PCR revealed a 2.5-fold increase in C3 expression in the Ccl2−/−/Cx3cr1−/−. While the retinas of four month old WT and Ccl2−/− showed minimal immunoreactivity for markers of macrophages and microglia, infiltrates of these mononuclear phagocytic cells were detected in the Ccl2−/−/Cx3cr1−/−retinal lesions and a few foci in the Cx3cr1−/− retina. The Ccl2−/−/Cx3cr1−/− had reduced toll-like receptor 4 (TLR4) expression in the RPE. Following LPS injection, the Ccl2−/−/Cx3cr1−/− had significantly reduced endotoxin-induced uveitis scores and showed a diminished increase in Tlr4 mRNA expression. No changes in TLR4 expression were detected in either single KO. Autoantibodies against the retina and photoreceptors were also detected in the Ccl2−/−/Cx3cr1−/− serum. Real-time RT-PCR revealed significant increases in Ccl5 transcript in the Ccl2−/−/Cx3cr1−/− relative to the WT. These results suggest that innate immunity and possibly adaptive immunity play an important role in Ccl2−/−/Cx3cr1−/− retinal degeneration. Moreover, since human AMD patients show similar immunopathological profiles, these results support the Ccl2−/−/Cx3cr1−/− as a suitable model for human AMD.