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Cited by 582Retinal Diseases and TreatmentsRetinal Development and DisordersRetinal Imaging and Analysis

Molecular pathology of age-related macular degeneration

Open access
Ding, Xiaoyan, Patel, Mrinali, Chan, Chi-Chao·2009·Progress in Retinal and Eye Research
DOI 10.1016/j.preteyeres.2008.10.001PMC PMC2715284
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Abstract

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the world. Although the etiology and pathogenesis of AMD remain largely unclear, a complex interaction of genetic and environmental factors is thought to exist. 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. Recent research on the genetic and molecular underpinnings of AMD brings to light several basic molecular pathways and pathophysiological processes that might mediate AMD risk, progression, and/or response to therapy. This review summarizes, in detail, the molecular pathological findings in both humans and animal models, including genetic variations in CFH, CX3CR1, and ARMS2/HtrA1, as well as the role of numerous molecules implicated in inflammation, apoptosis, cholesterol trafficking, angiogenesis, and oxidative stress.

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Crossref · 10.1016/j.preteyeres.2008.10.001

Cites

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Claims the paper makes

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  • Findingcitation

    In 148 advanced AMD patients and 162 control subjects with infection, no relationship was found between the risk-conferring CFH variant and C. pneumoniae.

    “We recently found no relationship between risk-conferring CFH variant and C. pneumoniae in 148 advanced AMD patients and 162 control subjects with the infection”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shen et al., 2008

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  • Findingcitation

    There is a positive association between AMD and C. pneumoniae infection, with 20% versus 10% positive C. pneumoniae DNA detected in blood of AMD patients compared with controls.

    “although there is a positive association between AMD and C. pneumoniae infection (20% vs. 10% positive C. pneumoniae DNA detected in the blood of AMD patients compared with the controls) (Shen et al., 2008).”
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    • cites Shen et al., 2008

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  • Findingcitation

    CX3CR1 transcript and protein in AMD maculae were undetectable or expressed at much lower levels than in normal eyes.

    “This previous study showed that CX3CR1 transcript and protein in the AMD maculae were undetectable or expressed at much lower levels than their SNP-type counterparts in the normal eyes.”
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    • cites Chan et al., 2005

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  • Findingcitation

    CX3CR1 expression is lower in the macula compared with the perimacular retina in AMD eyes bearing T280M.

    “we found lowered CX3CR1 expression in the macula compared with the perimacular retina of AMD eyes bearing T280M.”
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    • cites Chan et al., 2005

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  • Findingcitation

    In normal eyes, macular cells from an individual bearing the at-risk T/M280 allele exhibited lower CX3CR1 transcript expression than an individual bearing the wild-type T280T allele.

    “In normal eyes, macular cells from an individual bearing “at risk” allele T/M280 exhibited lower CX3CR1 transcript expression than an individual bearing “wild type or major” allele T280T.”
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    • cites Chan et al., 2005

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  • May combine two claims. 58
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    Findingcitation

    The V249I and T280M CX3CR1 SNPs confer increased risk of AMD, with odds ratios of 1.86 (1.04-3.31) for V249I and 1.94 (1.02-3.69) for T280M.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tuo et al., 2004 source

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    Findingcitation

    rs11200638 is associated with dry AMD with an odds ratio of 2.17 and wet AMD with an odds ratio of 2.97.

    “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).”
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    • cites Tuo et al., 2008 source

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    Findingcitation

    Macrophage and microglial accumulation is increased relative to wild-type in Ccl2/Cx3cr1 double knockout mice and in Cx3cr1 knockout mice, though less so in the latter.

    “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).”
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    • cites Ross et al., 2008 source

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    Findingcitation

    Ccl2/Cx3cr1 double knockout mice exhibit fundoscopically visible drusen-like lesions at 4-6 weeks of age, histological AMD signs including Bruch's membrane thickening, drusen, local RPE hypopigmentation and degeneration, photoreceptor disorganization and atrophy, and CNV in some mice.

    “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.”
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    • cites Chan et al., 2008 source

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    • cites Tuo et al., 2007 source

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    Premisenone given

    AMD pathology involves degeneration of retinal photoreceptors, retinal pigment epithelium, Bruch's membrane, and in some cases choroidal capillaries.

    “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.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Antioxidants, nuts, fish, and omega-3 polyunsaturated fatty acids have protective effects against AMD.

    “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).”
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    • cites AREDS, 2001 source

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    • cites Cho et al., 2001 source

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    • cites Seddon et al., 1994 source

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    Premisecitation

    Both fat intake and obesity are linked to increased risk of AMD.

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

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    • cites Seddon et al., 2003 source

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    Premisenone given

    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.

    “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”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Age-related changes in mouse RPE and choroid include recruitment of leukocytes and activation of the complement cascade.

    “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).”
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    • cites Chen et al., 2008 source

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    Premisecitation

    Recurrence risks in relatives of AMD cases are increased: siblings 2.95, first cousins 1.29, second cousins 1.13, and parents 5.66.

    “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).”
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    • cites Luo et al., 2008 source

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    Premisecitation

    Larger drusen, greater area covered by drusen, and larger areas of RPE hyperpigmentation and hypopigmentation in the macula increase the risk of late AMD.

    “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).”
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    • cites Klein et al., 2002 source

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    Premisecitation

    Aging is associated with retinal changes including alterations in RPE cell size and shape, thickening of Bruch's membrane, thickening of the internal limiting membrane, and a decrease in retinal neuronal elements.

    “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).”
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    • cites Green, 1996

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    Premisecitation

    Basal linear deposits consist of vesicular material in the inner collagenous zone of Bruch's membrane and represent a specific marker for AMD.

    “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).”
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    • cites Curcio and Millican, 1999

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    Premisecitation

    Recent studies have generated significant interest in the inflammatory underpinnings of AMD pathogenesis.

    “recent studies have generated significant interest in the inflammatory underpinnings of AMD pathogenesis (Klein et al., 2008b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Klein et al., 2008b

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    Premisenone given

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

    “These SNPs lie in genes encoding complement factors, chemokines and chemokine receptors, and toll-like receptors.”
    Quote in the paperNot a substantial claim

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    Premisereasoning

    Loss of RPE cells leads to gradual degeneration of nearby photoreceptors, thinning of the retina, and progressive visual impairment.

    “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.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Retinal angiomatous proliferation refers to new vessel development extending outward into the subretinal space from the neurosensory retina, sometimes anastomosing with choroid-derived vessels.

    “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).”
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    • cites Lafaut et al., 2000 source

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    Premisenone given

    Classical neovascular AMD is mainly illustrated by CNV and subretinal neovascular fibrous tissue.

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

    Choroidal neovascularization is the defining characteristic of late stage wet or neovascular AMD.

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

    Drusen are the hallmark lesions of AMD.

    “it has long been recognized that drusen are the hallmark lesions of AMD.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    CFH inhibits the alternative pathway by promoting Factor I-mediated inactivation of C3b or by displacing Factor Bb from the C3bBb complex.

    “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).”
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    • cites Alsenz et al., 1985 source

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    Premisecitation

    Yu et al. found no significant difference between Y and H CFH variants in protein secretion, cofactor activity, or heparan interaction, but a significant difference in CRP binding.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yu et al., 2007

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    Premisecitation

    CFH is encoded within chromosome 1q23-32, a region previously associated with AMD through linkage studies.

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

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    Premisecitation

    AMD patients have increased serum anti-C. pneumoniae antibodies, and these antibodies are linked to increased risk of AMD progression.

    “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).”
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    • cites Robman et al., 2005 source

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    Premisecitation

    CFH binds to denatured rather than native CRP, casting doubt on the link between CFH and CRP.

    “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).”
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    • cites Hakobyan et al., 2008 source

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    Premisecitation

    The L9H BF/E318D C2 and R32Q BF/intronic C2 variants are protective for AMD, with odds ratios of 0.45 and 0.36, respectively.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gold et al., 2006 source

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    Interpretationreasoning

    Current data suggest a central role for innate immunity and inflammation in general, and complement overactivation in particular, in AMD pathogenesis.

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

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    Premisecitation

    In AREDS patients, an interaction was observed between CFH Y402H genotype and antioxidant plus zinc supplementation: in YY homozygotes, 34% of placebo-treated progressed to advanced AMD versus 11% of antioxidant-plus-zinc-treated; in HH homozygotes, 44% of placebo-treated progressed versus 39% of treated.

    “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”
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    • cites Klein et al., 2008a

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    Premisecitation

    Variation near the FI gene on chromosome 4q25 is associated with risk of advanced AMD, although no obvious functional variation has been discovered.

    “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).”
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    • cites Fagerness et al., 2008

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    Premisecitation

    C3F has been associated with membranoproliferative glomerulonephritis type II.

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

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    Premisecitation

    The IL8 A251T genetic polymorphism is associated with AMD, with the homozygous AA genotype as the at-risk factor.

    “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).”
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    • cites Goverdhan et al., 2008 source

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    Premisecitation

    CX3CR1 is expressed on all retinal microglial cells, and these cells are the only cells in the retina that express CX3CR1.

    “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.”
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    • cites Combadiere et al., 2007 source

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    Premisecitation

    The D299G TLR4 polymorphism leads to increased AMD risk, with an odds ratio of 2.65.

    “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).”
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    • cites Zareparsi et al., 2005 source

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    Premisecitation

    The finding of an AMD susceptibility locus on chromosome 10q26 has been replicated by other genome-wide linkage studies and supported by a genome-scan meta-analysis.

    “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).”
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    • cites Weeks et al., 2004 source

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    • cites Fisher et al., 2005 source

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    Premisecitation

    The D299G TLR4 variant has been linked to impaired LPS responsiveness in mice, which is reversible by TLR4 overexpression.

    “Functionally, the D299G TLR4 variant has been linked to impaired LPS responsiveness in mice, which is reversible by TLR4 overexpression (Arbour et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Arbour et al., 2000 source

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  • May combine two claims.

    Interpretationreasoning

    The relationships between SNPs in TLR genes and AMD remain preliminary or controversial and need further studies in larger, diverse populations.

    “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.”
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    Premisecitation

    rs11200638 in the HtrA1 promoter is the most well-documented, statistically significant AMD-associated SNP, with odds ratios of 1.60-2.61 in heterozygous and 6.56-10.0 in homozygous individuals (Caucasians, Chinese, Japanese).

    “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).”
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    • cites Cameron et al., 2007 source

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    • cites Deangelis et al., 2008 source

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    • cites Dewan et al., 2006 source

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    Premisecitation

    Human donor AMD eyes contain higher levels of protein adducts from oxidative modification of carbohydrates and lipids and higher levels of antioxidant enzymes compared with non-AMD eyes.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Crabb et al., 2002 source

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    • cites Howes et al., 2004 source

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    • cites Decanini et al., 2007 source

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    Interpretationreasoning

    Mitochondria play a central role in aging and in the pathogenesis of AMD.

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

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    Premisecitation

    ARMS2 protein in the human retina localizes to the photoreceptor layer and co-localizes with a mitochondrial marker, suggesting mitochondrial expression.

    “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).”
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    • cites Fritsche et al., 2008 source

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    Premisenone given

    The A69S and InDel are in 100% linkage disequilibrium and on the same haplotype, so their effects are not independent.

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

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    Premisecitation

    Therapies targeting VEGF have shown significant improvement of central vision and reduction of CNV.

    “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).”
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    • cites Wylegala and Teper, 2007

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    Premisecitation

    ARMS2 (A69S), rather than HtrA1, is truly associated with AMD.

    “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).”
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    • cites Kanda et al., 2007 source

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    Premisecitation

    VEGF is a key molecule in promoting angiogenesis.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ferrara et al., 2003 source

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    Premisecitation

    The ERCC6 C6530G SNP is modestly associated with AMD susceptibility, and its interaction with a SNP (rs380390) in the CFH intron is highly associated with AMD.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tuo et al., 2006 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Conflicting data on VEGF-A association with AMD could result from differences in ethnicities studied, study designs, and statistical analyses.

    “These conflicting data could result from differences of the ethnicities studied, study designs, and statistical analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The RPE cell is one of many systems that downregulate the immune response in the eye, and the pathway between RPE damage and ocular inflammation is likely bidirectional.

    “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.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Neovascular AMD is associated with the rs2010963 (G634C) VEGF-A SNP and with two intronic VEGF-A SNPs (rs833070 and rs3025030).

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Haines et al., 2006 source

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  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The mouse retina has no macula.

    “The main drawback of using mice to study AMD is that the mouse retina has no macula.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Cx3cr1 knockout mice show increased microglial accumulation after laser injury, worsened laser-induced CNV, and retinal degeneration.

    “Moreover, Cx3cr1−/− mice exhibited increased microglial accumulation after laser-injury, as well as worsened laser-induced CNV and retinal degeneration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Combadiere et al., 2007 source

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    Premisecitation

    Cx3cr1 knockout mice show retinal degeneration and drusen-like deposits containing bloated microglia that can phagocytose photoreceptor outer segments in mice aged 18 months and older.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Combadiere et al., 2007 source

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    Premisecitation

    Microglia are resident immune cells in the retina required for neuronal homeostasis and innate immune defense.

    “Microglia are the resident immune cells in the retina required for neuronal homeostasis and innate immune defense (Langmann, 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Langmann, 2007 source

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  • May combine two claims.

    Interpretationown data

    Animal models based on Ccl2 and Cx3cr1 knockout have strengthened the hypothesis and provided insights into potential inflammatory mechanisms underlying AMD pathogenesis.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    These findings are consistent with human AMD drusen findings and with a critical role of complement overactivity in AMD.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hageman et al., 2005 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    CFH polymorphisms are associated with susceptibility to AMD in more than half of affected individuals.

    “As discussed above, CFH polymorphisms are associated with susceptibility to AMD in more than half of affected individuals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The Ccl2/Cx3cr1 double knockout mouse model of AMD is robust and has several immunological features also documented in human AMD and supported by other in vivo AMD models.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Funduscopic examination and vasculature appear normal in cfh knockout mice.

    “Funduscopic examination and vasculature, however, appears normal in the cfh−/− mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Coffey et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CNV in aged ApoE4 mice on the high fat cholesterol rich diet contains amyloid β deposits, VEGF, and other factors also seen in human AMD and CNV.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Malek et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    cfh knockout mice show increased autofluorescence, C3 accumulation, disorganization of photoreceptor outer segments, thinning of Bruch's membrane, and increased RPE organelles.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Coffey et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Prior studies suggest a probable association between ApoE polymorphisms and AMD.

    “As discussed above, prior studies have suggested a probable association between ApoE polymorphisms and AMD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Aged ApoE4 mice on a high fat cholesterol rich diet exhibit several features of human AMD, including drusen, Bruch's membrane thickening, geographic RPE atrophy, and CNV.

    “Aged ApoE4 mice on this diet exhibited several features of human AMD, including drusen, thickening of Bruch’s membrane, geographic RPE atrophy, and CNV.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Malek et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Eyes of ApoE2 transgenic mice express higher levels of VEGF and lower levels of PEDF.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lee et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Abcr knockout mice demonstrate decreased dark adaptation, increased all-trans-retinaldehyde after light exposure, increased phosphatidylethanolamine in outer segments, accumulation of N-retinylidene-phosphatidylethanolamine in photoreceptors, and deposition of A2E fluorophore in the RPE.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Weng et al., 1999 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The ApoE-based murine model of AMD highlights a potential role for cholesterol metabolism in AMD pathogenesis and emphasizes the need to clarify the role of ApoE variants in human AMD.

    “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.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    Although age, race, smoking, and diet have been linked to AMD, the etiology and pathogenesis of the disease remain largely unclear.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisenone given

    Our understanding of AMD pathogenesis remains largely incomplete.

    “Though AMD research has made great advances in recent years, our understanding of its pathogenesis remains largely incomplete.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

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

    “CFH polymorphisms have been linked to a pro-inflammatory state, including increased CRP and decreased complement inhibitory effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

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

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Epidemiological studies strengthen the role of oxidative stress by showing increased AMD risk with smoking and decreased risk with antioxidant-rich diets such as lutein/zeaxanthin.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Treatment options for AMD are limited.

    “Treatment options for the condition are similarly limited.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    AMD lesions classically show signs of persistent chronic inflammatory damage, including mild macrophage infiltration, microglial accumulation, and inflammatory components such as complement factors and pro-inflammatory cytokines/chemokines in drusen and AMD lesions.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    AMD is a debilitating retinal disease that manifests clinically with loss of central vision and pathologically with drusen accumulation, RPE degeneration, photoreceptor atrophy, and in some cases CNV.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ultrastructural analysis reveals abnormal basal RPE with small irregular dense bodies in both abcr knockout and heterozygous mice, but no drusen formation.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mata et al., 2001

      Not checked in the free run.

73 of 73

  • The paper relies on this without support.

    Innovation in AMD pharmacotherapy depends largely on a thorough understanding of the molecular mechanisms underlying AMD pathogenesis.

    “Innovation in AMD pharmacotherapy, in turn, depends largely upon a thorough understanding of the molecular mechanisms underlying AMD pathogenesis.”

  • The paper relies on this without support.

    AMD is a multifactorial disease that primarily affects photoreceptors and RPE cells.

    “AMD is a multifactorial disease that affects primarily the photoreceptors and RPE cells.”

  • The paper relies on this without support.

    The mouse retina has no macula.

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

  • The paper relies on this without support.

    Laser-induced CNV and CNV associated with age-related degenerative retinal changes arise through different mechanisms.

    “These studies might be reconciled by the argument that laser-induced CNV, an acute injury, occurs by a different mechanism than CNV associated with age-related degenerative changes in the retina.”

  • The paper relies on this without support.

    Many critical biological processes are context specific.

    “Given the context specificity of many critical biological processes and the fact that most common diseases including AMD are thought to be the outcome of a complex interaction between many genetic loci and the environment, it follows that there are obvious advantages to studying gene expression in cells and tissues that represent the in vivo state.”

  • The paper relies on this without support.

    Common diseases including AMD result from complex interactions between many genetic loci and the environment.

    “Given the context specificity of many critical biological processes and the fact that most common diseases including AMD are thought to be the outcome of a complex interaction between many genetic loci and the environment, it follows that there are obvious advantages to studying gene expression in cells and tissues that represent the in vivo state.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The four SNPs studied have consistently shown the strongest associations with AMD development and progression and have been postulated to influence treatment response.

    “Although other susceptibility genes have been reported, these four SNPs have consistently been shown to have the strongest associations with the development and progression of AMD and have been postulated to influence response to therapy.2,3,12”

    From Pharmacogenetics for Genes Associated with Age-related Macular Degeneration in the Comparison of AMD Treatments Trials (CATT) (2013) · cites this paper as [2]

    Sections 3.2 and 3.4 report strong associations of particular CFH, ARMS2, and HtrA1 variants with AMD risk, and section 7 reports that a risk-conferring CFH variant was associated with reduced response to antioxidant and zinc therapy. The paper does not establish that the citing study’s four SNPs, as a group, consistently have the strongest associations with both AMD development and progression or that all four may influence treatment response. No page numbers were provided in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Numerous SNPs in multiple genes have been associated with the prevalence of early and/or late AMD.

    “Pioneering developments in AMD genetics research have identified numerous single nucleotide polymorphisms (SNPs) in multiple genes associated with the prevalence of the early and/or late stages of AMD.2,3”

    From Pharmacogenetics for Genes Associated with Age-related Macular Degeneration in the Comparison of AMD Treatments Trials (CATT) (2013) · cites this paper as [2]

  • Overexpression of HTRA1 has been hypothesized to alter Bruch's membrane integrity and favor CNV development.

    “It has been hypothesized that overexpression of HTRA1 may alter the integrity of Bruch’s membrane and favor the development of CNV.2”

    From Pharmacogenetics for Genes Associated with Age-related Macular Degeneration in the Comparison of AMD Treatments Trials (CATT) (2013) · cites this paper as [2]

  • Loss of mitochondria is reported in AMD retina.

    “Loss of mitochondria is also reported in AMD retina (Ding et. al, 2009).”

    From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Ding et. al, 2009

  • AMD still has an unknown etiology, though oxidative stress to RPE cells along with immune dysregulation are leading theories of AMD pathogenesis.

    “AMD still has an unknown etiology, though oxidative stress to the retinal pigment epithelium (RPE) cells along with immune dysregulation are leading theories of AMD pathogenesis (Ding et al., 2009).”

    From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Ding et al., 2009

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Brantley study's treatment differs from its reference title

    Minor

    The text attributes a bevacizumab treatment-response analysis to Brantley et al., while the cited reference identifies the treatment as photodynamic therapy.

1 of 1

Cites

Flagged first, then by citations

8 of the 224 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. de Jong, 2007, Polymorphisms in the Vascular Endothelial Growth Factor Gene and Risk of Aging Macula Disorder: The Rotterdam Study, Invest. Ophthalmol. Vis. Sci., 48
  2. Green, 1996, Retina: growth and aging, Vol. 2, 676
  3. Hutchison, 1875, Symmetrical central choroidoretinal disease occurring in senile persons, R. Lond. Ophthal. Hosp. Rep, 8, 231

Cited by

Sorted by citations

Related

Authors
Ding, X., Patel, M., & Chan, C.-C.
Affiliations
National Institutes of Health (US)
Corresponding author
Chan, Chi-Chao
ORCID
Venue
Progress in Retinal and Eye Research
Publisher
Elsevier BV
Published
2009-01
Volume
28
Issue
1
Pages
1-18
ISSN
1350-9462 (ISSN-L)
DOI
10.1016/j.preteyeres.2008.10.001
PMC
PMC2715284
OpenAlex
W2084944408
Semantic Scholar
f9eb706832ee615a7771dad2f6ed351095c05219
Cited by
582
References
224
Citations by year
2026: 5 · 2025: 21 · 2024: 17 · 2023: 16 · 2022: 24 · 2021: 43 · 2020: 20 · 2019: 34 · 2018: 34 · 2017: 36 · 2016: 33 · 2015: 39 · 2014: 39 · 2013: 44 · 2012: 53
FWCI
7.86
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Progress in Retinal and Eye Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Eye Institute (Z01EY000222, Z01EY000418)
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
Keywords
age-related macular degeneration, molecular pathology, genetic susceptibility, complement factor H, CX3CR1, inflammation, apoptosis, cholesterol transport, angiogenesis, oxidative stress, retinal pigment epithelium, Bruch's membrane, choroidal capillaries, photoreceptor degeneration, animal models
MeSH terms
Animals, Disease Models, Animal, Humans, Macular Degeneration, Retina, Polymorphism, Single Nucleotide

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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