Molecular pathology of age-related macular degeneration

In the paper

“We have reported that the V249I (valine to isoleucine at amino acid 249) and T280M (threonine to methionine at amino acid 280) CX3CR1 SNPs confer increased risk of AMD (Tuo et al., 2004). The OR (CI) of these two SNPs were 1.86 (1.04–3.31) for V249I and 1.94 (1.02–3.69) for T280M.”

What the sources say

• Not checked yetcites Tuo et al., 2004 source

In the paper

“By examining four cohort studies, we have also confirmed this association with ORs of 2.17 and 2.97 for dry and wet AMD, respectively (Tuo et al., 2008).”

What the sources say

• Not checked yetcites Tuo et al., 2008 source

In the paper

“Macrophage and microglial accumulation was also increased relative to wild-type in Ccl2−/−/Cx3cr1−/− mice, as well as in Cx3cr1−/− mice, though to a lesser degree (Ross et al., 2008).”

What the sources say

• Not checked yetcites Ross et al., 2008 source

In the paper

“We found that Ccl2−/−/Cx3cr1−/− mice exhibited, at an early age of 4–6 weeks, fundoscopically visible drusen-like lesions, as well as histological signs of AMD such as thickening of Bruch’s membrane, drusen, local RPE hypopigmentation and degeneration, and photoreceptor disorganization and atrophy, as well as CNV in some mice.”

What the sources say

• Not checked yetcites Chan et al., 2008 source
• Not checked yetcites Tuo et al., 2007 source

In the paper

“AMD pathology is characterized by degeneration involving the retinal photoreceptors, retinal pigment epithelium, and Bruch’s membrane, as well as, in some cases, alterations in choroidal capillaries.”

In the paper

“analyses have revealed protective effects from antioxidants, nuts, fish, and omega-3 polysaccharide unsaturated fatty acids (AREDS, 2001; Cho et al., 2001; Seddon et al., 1994, 2001; Smith et al., 2000).”

What the sources say

• Not checked yetcites AREDS, 2001 source
• Not checked yetcites Cho et al., 2001 source
• Not checked yetcites Seddon et al., 1994 source

In the paper

“Both fat intake and obesity have been linked to increased risk of AMD (Mares-Perlman et al., 1995; Seddon et al., 2003)”

What the sources say

• Not checked yetcites Mares-Perlman et al., 1995 source
• Not checked yetcites Seddon et al., 2003 source

In the paper

“Early AMD is characterized by thickening and loss of normal architecture within Bruch’s membrane, lipofuscin accumulation in the RPE, and drusen formation beneath the RPE in Bruch’s membrane”

In the paper

“A recent study of age-related changes demonstrates recruitment of leukocytes and activation of the complement cascade in mouse RPE and choroid (Chen et al., 2008).”

What the sources say

• Not checked yetcites Chen et al., 2008 source

In the paper

“Recurrence risks in relatives indicate increased relative risks in siblings (2.95), first cousins (1.29), second cousins (1.13), and parents (5.66) of affected cases (Luo et al., 2008).”

What the sources say

• Not checked yetcites Luo et al., 2008 source

In the paper

“The larger the drusen, the greater the area they cover, and the larger the areas of hyperpigmentation and hypopigmentation of the RPE in the macula, the higher the risk of late age-related macular degeneration is (Klein et al., 2002).”

What the sources say

• Not checked yetcites Klein et al., 2002 source

In the paper

“Aging is associated with changes in the retina, including alterations in RPE cellular size and shape, thickening of Bruch’s membrane, thickening of the internal limiting membrane, and a decrease in retinal neuronal elements (Green, 1996).”

What the sources say

• Not checked yetcites Green, 1996

In the paper

“BlinL consist of vesicular material located in the inner collagenous zone of Bruch’s membrane and represent a specific marker for AMD (Curcio and Millican, 1999).”

What the sources say

• Not checked yetcites Curcio and Millican, 1999

In the paper

“recent studies have generated significant interest in the inflammatory underpinnings of AMD pathogenesis (Klein et al., 2008b).”

What the sources say

• Not checked yetcites Klein et al., 2008b

In the paper

“These SNPs lie in genes encoding complement factors, chemokines and chemokine receptors, and toll-like receptors.”

In the paper

“Loss of RPE cells responsible for servicing the overlying photoreceptors leads to the gradual degeneration of nearby photoreceptors, resulting in thinning of the retina (Fig. 2) and a progressive visual impairment.”

In the paper

“RAP refers to new vessel development extending outward into the subretinal space from the neurosensory retina, sometimes anastomosing with the choroid-derived vessels (Lafaut et al., 2000).”

What the sources say

• Not checked yetcites Lafaut et al., 2000 source

In the paper

“Classical neovascular AMD is mainly illustrated with CNV and subretinal neovascular fibrous tissue (Fig. 3).”

In the paper

“Choroidal neovascularization (CNV) is the defining characteristic of late stage ‘wet’ or neovascular AMD.”

In the paper

“it has long been recognized that drusen are the hallmark lesions of AMD.”

In the paper

“CFH inhibits the alternative pathway by promoting Factor I-mediated inactivation of C3b or by displacing Factor Bb from the C3bBb complex (Alsenz et al., 1985).”

What the sources say

• Not checked yetcites Alsenz et al., 1985 source

In the paper

“Yu et al. also show no significant difference in their protein secretion, cofactor activity, or interaction with heparan, but a significant difference in binding to CRP (Yu et al., 2007).”

What the sources say

• Not checked yetcites Yu et al., 2007

In the paper

“CFH is encoded within the interval of chromosome 1q23–32, a region associated with AMD previously through linkage studies (Klein et al., 1998).”

What the sources say

• Not checked yetcites Klein et al., 1998 source

In the paper

“AMD patients have been found to possess increased serum anti-C. pneumoniae antibodies, and these antibodies have been linked to increased risk of AMD progression (Robman et al., 2005).”

What the sources say

• Not checked yetcites Robman et al., 2005 source

In the paper

“a recent publication indicates that CFH binds to the denatured rather than native CRP, thus casting some doubt upon this link between CFH and CRP (Hakobyan et al., 2008).”

What the sources say

• Not checked yetcites Hakobyan et al., 2008 source

In the paper

“the L9H BF/E318D C2 and R32Q BF/intronic variants of C2 have been shown to be protective for AMD (odds ratio (OR) = 0.45 and 0.36, respectively) by Gold et al.”

What the sources say

• Not checked yetcites Gold et al., 2006 source

In the paper

“the current data suggest a central role for innate immunity and inflammation in general and complement overactivation in particular for AMD pathogenesis.”

In the paper

“In individuals homozygous for the non-risk phenotype (Y402Y/Y402Y), 34% of those treated with placebo progressed to advanced AMD, compared with 11% of those treated with antioxidants plus zinc, a reduction of approximately 68%. In contrast, in individuals homozygous for the risk-conferring phenotype (Y402H/Y402H), 44% of those treated with placebo group progressed to advanced AMD, compared with 39”

What the sources say

• Not checked yetcites Klein et al., 2008a

In the paper

“Variation near the FI gene on chromosome 4q25 is associated with risk of advanced AMD, although no obvious functional variation has been discovered (Fagerness et al., 2008).”

What the sources say

• Not checked yetcites Fagerness et al., 2008

In the paper

“C3F has in fact been associated with several diseases, including membranoproliferative glomerulonephritis type II (Montes et al., 2008).”

What the sources say

• Not checked yetcites Montes et al., 2008 source

In the paper

“The interleukin-8 (IL8) A251T genetic polymorphism located in chromosome 4q13–21 is reported to be associated with AMD, with the homozygous AA genotype (A allele) as the “at risk” factor (Goverdhan et al., 2008).”

What the sources say

• Not checked yetcites Goverdhan et al., 2008 source

In the paper

“whose immunohistochemical analysis in humans showed that CX3CR1 was expressed on all retinal microglial cells, and these cells are the only cells in the retina that express CX3CR1.”

What the sources say

• Not checked yetcites Combadiere et al., 2007 source

In the paper

“A study by Zareparsi et al reported that the D299G (aspartate to glycine at amino acid 299) TLR4 (encoded in chromosome 9q32–33) polymorphism leads to increased AMD risk (OR = 2.65) (Zareparsi et al., 2005).”

What the sources say

• Not checked yetcites Zareparsi et al., 2005 source

In the paper

“This finding of an AMD susceptibility locus on chromosome 10q26 has been replicated by other genome-wide linkage studies (Weeks et al., 2004) and supported by a genome-scan meta-analysis (Fisher et al., 2005).”

What the sources say

• Not checked yetcites Weeks et al., 2004 source
• Not checked yetcites Fisher et al., 2005 source

In the paper

“Functionally, the D299G TLR4 variant has been linked to impaired LPS responsiveness in mice, which is reversible by TLR4 overexpression (Arbour et al., 2000).”

What the sources say

• Not checked yetcites Arbour et al., 2000 source

In the paper

“In general, the relationships of these SNPs with AMD are still preliminary or controversial to date and require additional studies in diverse and larger populations.”

In the paper

“Several studies have shown that rs11200638 in the promoter region is the most well-documented, statistically significant AMD-associated SNP with a high OR of 1.60–2.61 and 6.56–10.0 in heterozygous and homozygous individuals (Caucasians, Chinese and Japanese), respectively (Cameron et al., 2007; Deangelis et al., 2008; Dewan et al., 2006; Mori et al., 2007; Tam et al., 2008; Yang et al., 2006).”

What the sources say

• Not checked yetcites Cameron et al., 2007 source
• Not checked yetcites Deangelis et al., 2008 source
• Not checked yetcites Dewan et al., 2006 source

In the paper

“First, studies have shown that human donor AMD eyes contain higher levels of protein adducts resulting from the oxidative modification of carbohydrates and lipids (Crabb et al., 2002; Howes et al., 2004) and higher levels of antioxidant enzymes (Decanini et al., 2007; Frank et al., 1999) compared with non-AMD eyes, which indicate that oxidative stress plays an important role in AMD.”

What the sources say

• Not checked yetcites Crabb et al., 2002 source
• Not checked yetcites Howes et al., 2004 source
• Not checked yetcites Decanini et al., 2007 source

In the paper

“Several lines of evidence indicate that mitochondria play a central role in aging and in the pathogenesis of AMD.”

In the paper

“Fritsche et al. also showed that ARMS2 protein in the human retina localizes to the photoreceptor layer and that it demonstrates a minor dot-like staining in the ellipsoid region of the rod and cone inner segments, which fully co-localizes with a mitochondrial marker, anti-MTCO2, suggesting that ARMS2 is expressed in the mitochondria (Fritsche et al., 2008).”

What the sources say

• Not checked yetcites Fritsche et al., 2008 source

In the paper

“Most importantly, since the A69S and InDel are in 100% LD and on the same haplotype, the effects are not independent to each other.”

In the paper

“VEGF plays a critical role in the pathogenesis of neovascular AMD, and recently, therapies targeting VEGF have shown promising results of significant improvement of central vision and reduction of CNV (Wylegala and Teper, 2007).”

What the sources say

• Not checked yetcites Wylegala and Teper, 2007

In the paper

“Recently Kanda et al. reported that ARMS2 (T allele at rs10490924, A69S), rather than HtrA1, to be truly associated with AMD (Kanda et al., 2007).”

What the sources say

• Not checked yetcites Kanda et al., 2007 source

In the paper

“It is well established that the formation of blood vessels occurs by angiogenesis and that vascular endothelial growth factor (VEGF) is a key molecule in promoting angiogenesis (Ferrara et al., 2003).”

What the sources say

• Not checked yetcites Ferrara et al., 2003 source

In the paper

“One study has demonstrated that the ERCC6 C6530G SNP is modestly associated with AMD susceptibility, its interaction with a SNP (rs380390) in the CFH intron is highly associated with AMD (Tuo et al., 2006).”

What the sources say

• Not checked yetcites Tuo et al., 2006 source

In the paper

“These conflicting data could result from differences of the ethnicities studied, study designs, and statistical analyses.”

In the paper

“Indeed, the RPE cell is one of many systems that downregulate the immune response in the eye, and thus the pathway between RPE damage and ocular inflammation is likely a two way street whereby RPE damage potentiates inflammation, which further worsens RPE degeneration.”

In the paper

“Neovascular AMD was found to be associated with the rs2010963 (G634C) VEGF-A SNP in a case-control cohort, and in a family cohort with two intronic VEGF-A SNPs (rs833070 and rs3025030) (Haines et al., 2006).”

What the sources say

• Not checked yetcites Haines et al., 2006 source

In the paper

“The main drawback of using mice to study AMD is that the mouse retina has no macula.”

In the paper

“Moreover, Cx3cr1−/− mice exhibited increased microglial accumulation after laser-injury, as well as worsened laser-induced CNV and retinal degeneration.”

What the sources say

• Not checked yetcites Combadiere et al., 2007 source

In the paper

“Cx3cr1−/− mice demonstrated retinal degeneration and drusen-like deposits, which contained bloated accumulated microglia capable of phagocytosing outer segments of photoreceptor cells in 18 months and older mice.”

What the sources say

• Not checked yetcites Combadiere et al., 2007 source

In the paper

“Microglia are the resident immune cells in the retina required for neuronal homeostasis and innate immune defense (Langmann, 2007).”

What the sources say

• Not checked yetcites Langmann, 2007 source

In the paper

“Animal models based upon Ccl2 and Cx3cr1 knockout have lent strength to this hypothesis and provided some insights into the potential inflammatory mechanisms underlying AMD pathogenesis.”

In the paper

“These findings are consistent with findings in drusen of humans with AMD (Hageman et al., 2005), as well as the critical role in AMD of complement overactivity, which has been discussed above.”

What the sources say

• Not checked yetcites Hageman et al., 2005 source

In the paper

“As discussed above, CFH polymorphisms are associated with susceptibility to AMD in more than half of affected individuals.”

In the paper

“These findings highlight that the Ccl2−/−/Cx3cr1−/− murine model of AMD is a robust one with several immunological features also documented in human AMD and supported by studies in other in vivo models of AMD.”

In the paper

“Funduscopic examination and vasculature, however, appears normal in the cfh−/− mice.”

What the sources say

• Not checked yetcites Coffey et al., 2007 source

In the paper

“Moreover, CNV in aged ApoE4 mice on the HF-CR diet contained amyloid β deposits, as well as VEGF and other factors also seen in human AMD and CNV.”

What the sources say

• Not checked yetcites Malek et al., 2005 source

In the paper

“These mice also demonstrated increased autofluorescence, accumulation of C3, and disorganization of photoreceptor outer segments in the retina, as well as thinning of Bruch’s membrane and increased RPE organelles.”

What the sources say

• Not checked yetcites Coffey et al., 2007 source

In the paper

“As discussed above, prior studies have suggested a probable association between ApoE polymorphisms and AMD.”

In the paper

“Aged ApoE4 mice on this diet exhibited several features of human AMD, including drusen, thickening of Bruch’s membrane, geographic RPE atrophy, and CNV.”

What the sources say

• Not checked yetcites Malek et al., 2005 source

In the paper

“Moreover, the eyes of ApoE2 transgenic mice also expressed higher levels of the proangiogenic factor VEGF but lower levels of anti-angiogenic factor pigment epithelium derived factor (PEDF).”

What the sources say

• Not checked yetcites Lee et al., 2007

In the paper

“Abcr−/− mice demonstrate decreased dark adaptation, increased all-trans-retinaldehyde after light exposure, increased phosphatidylethanolamine (PE) in outer segments, accumulation of N-retinylidene-phosphatidylethanolamine, the conjugate of all-trans retinaldehyde and PE in photoreceptors, and deposition of A2E fluorophore, a major component of lipofuscin, in the RPE (Weng et al., 1999).”

What the sources say

• Not checked yetcites Weng et al., 1999 source

In the paper

“Most importantly, the ApoE-based murine model of AMD highlights the potential role for cholesterol metabolism in AMD pathogenesis and further emphasized the need to clarify the role of ApoE variants in human AMD.”

In the paper

“While several risk factors, including age, race, smoking, and diet have been linked to AMD, the etiology and pathogenesis of the disease remain largely unclear.”

In the paper

“Though AMD research has made great advances in recent years, our understanding of its pathogenesis remains largely incomplete.”

In the paper

“CFH polymorphisms have been linked to a pro-inflammatory state, including increased CRP and decreased complement inhibitory effect.”

In the paper

“VEGF is a key angiogenic factor in the development of CNV in late stage AMD, and recent studies suggest that polymorphisms in the VEGF gene might contribute to risk of AMD and to efficacy of anti-VEGF therapy.”

In the paper

“The role of oxidative stress is further strengthened by epidemiological studies demonstrating increased risk with smoking, a potent oxidizing stress, and decreased risk with diets rich in antioxidants such as lutein/zeaxanthin.”

In the paper

“Treatment options for the condition are similarly limited.”

In the paper

“Pathology of AMD lesions classically demonstrates signs of persistent chronic inflammatory damage, including not only mild infiltration of macrophages and accumulation of microglia, but also presence of inflammatory components such as complement factors and pro-inflammatory cytokines/chemokines in the drusen and AMD lesions.”

In the paper

“AMD is a debilitating disease of the retina, which manifests clinically with loss of central vision and pathologically with the accumulation of drusen, RPE degeneration, photoreceptor atrophy, and in some cases, with CNV.”

In the paper

“Ultrastructural analysis revealed abnormal basal RPE with small irregular dense bodies in both abcr−/− and abcr+/− mice, but no drusen formation (Mata et al., 2001).”

What the sources say

• Not checked yetcites Mata et al., 2001