Basal Linear Deposit and Large Drusen Are Specific for Early Age-Related Maculopathy

Curcio, Christine A.; Millican, C L

doi:10.1001/archopht.117.3.329

Cited by 338 publications

(274 citation statements)

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“…21,22 We previously reported that mice chronically exposed to HQ developed sub-RPE deposits and BrM thickening consistent with changes in early stages of human AMD. 57 Here, we found that RPE from these mice showed increased levels of phosphorylated Hsp25. However, in contrast to ARPE-19 cells, our results indicate that Hsp25 mRNA and protein levels were dramatically decreased in mice chronically exposed to HQ.…”

Section: Hsp27 and Oxidative Stress In Rpe 1209mentioning

confidence: 60%

Cigarette Smoke-Related Hydroquinone Induces Filamentous Actin Reorganization and Heat Shock Protein 27 Phosphorylation through p38 and Extracellular Signal-Regulated Kinase 1/2 in Retinal Pigment Epithelium

Pons

Cousins

Csaky

et al. 2010

The American Journal of Pathology

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Retinal pigment epithelium (RPE)-derived membranous debris named blebs, may accumulate and contribute to sub-RPE deposit formation, which is the earliest sign of age-related macular degeneration (AMD). Oxidative injury to the RPE might play a significant role in AMD. However, the underlying mechanisms are unknown. We previously reported that hydroquinone (HQ), a major pro-oxidant in cigarette smoke, foodstuff, and atmospheric pollutants, induces actin rearrangement and membrane blebbing in RPE cells as well as sub-RPE deposits in mice. Here, we show for the first time that phosphorylated Heat shock protein 27 (Hsp27), a key regulator of actin filaments dynamics, is up-regulated in RPE from patients with AMD. Also, HQ-induced nonlethal oxidative injury led to Hsp27mRNA up-regulation, dimer formation , and Hsp27 phosphorylation in ARPE-19 cells. Furthermore, we found that a cross talk between p38 and extracellular signal-regulated kinase (ERK) mediates HQ-induced Hsp27 phosphorylation and actin aggregate formation, revealing ERK as a novel upstream mediator of Hsp27 phosphorylation. Finally, we demonstrated that Hsp25, p38, and ERK phosphorylation are increased in aging C57BL/6 mice chronically exposed to HQ, whereas Hsp25 expression is decreased. Our data suggest that phosphorylated Hsp27 might be a key mediator in AMD and HQ-induced oxidative injury to the RPE, which may provide helpful insights into the early cellular events associated with actin reorganization and bleb formation involved in sub-RPE deposits formation relevant to the pathogenesis of AMD.

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Section: Hsp27 and Oxidative Stress In Rpe 1209mentioning

confidence: 60%

Cigarette Smoke-Related Hydroquinone Induces Filamentous Actin Reorganization and Heat Shock Protein 27 Phosphorylation through p38 and Extracellular Signal-Regulated Kinase 1/2 in Retinal Pigment Epithelium

Pons

Cousins

Csaky

et al. 2010

The American Journal of Pathology

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“…Basal deposits are the strongest histopathological marker of aging and age-related disease (Sarks, 1976;Green and Enger, 1993;Spraul et al, 1996;Spraul and Grossniklaus, 1997;Curcio and Millican, 1999). The location and composition of these deposits distinguish aging from AMD.…”

Section: Discussionmentioning

confidence: 99%

“…The location and composition of these deposits distinguish aging from AMD. Basal laminar deposits (BlamD), which form between the RPE cell and basement membrane, are a normal aging change early, but become specific for AMD when they become thick and contain cellular debris, 'long spaced collagen', membranous structures, lipid, and inflammatory proteins (Sarks, 1976;Newsome et al, 1987;Green and Enger, 1993;van der Schaft et al, 1994;Spraul et al, 1996;Spraul and Grossniklaus, 1997;Curcio and Millican, 1999;Anderson and Ozaki, 2001;Johnson et al, 2002;Leu et al, 2002). The most sensitive and specific histopathologic marker of AMD is basal linear deposits (BlinD), which form in the inner collagenous layer of Bruch's membrane.…”

Section: Discussionmentioning

confidence: 99%

“…The composition and location of these deposits distinguishes chronological aging from age-related disease. Basal laminar deposits, which develop between the RPE cell and basement membrane, are specific for age-related macular degeneration (AMD) when they are thick and contain heterogeneous debris such as long spaced collagen (Sarks, 1976;Newsome et al, 1987;Green and Enger, 1993;van der Schaft et al, 1994;Spraul et al, 1996;Spraul and Grossniklaus, 1997;Curcio and Millican, 1999;Anderson et al, 2001;Johnson et al, 2002;Leu et al, 2002). Basal linear deposits occur within the inner collagenous layer, and are the most specific basal deposit for AMD (Sarks, 1976;Newsome et al, 1987;Green and Enger, 1993;van der Schaft et al, 1994;Spraul et al, 1996;Spraul and Grossniklaus, 1997;Curcio and Millican, 1999;Anderson et al, 2001;Johnson et al, 2002;Leu et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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The expression of advanced glycation endproduct receptors in rpe cells associated with basal deposits in human maculas

Yamada

Ishibashi

et al. 2006

Experimental Eye Research

100

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Basal deposits within Bruch's membrane are associated with aging and age-related macular degeneration (AMD) although the factors causing their formation are incompletely understood. Advanced glycation endproducts (AGEs) accumulate in Bruch's membrane including basal deposits and drusen with aging. One mechanism by which AGEs alter a cell's phenotype is via AGE receptors. The purpose of this study was to immunolocalize and quantify the expression of AGE receptors by RPE cells associated with basal deposits or normal Bruch's membrane that were microdissected from human maculas. Postmortem eyes from 14 aged control donors and five donors with non-neovascular AMD were cryopreserved. RPE cells associated with normal Bruch's membrane or basal deposits were laser capture microdissected. The RNA was extracted and used for RT-qPCR to quantify the expression of RAGE, AGE R1, AGE R2, and AGE R3. Streptavidin alkaline phosphatase immunohistochemistry for these receptors was also performed and sections were bleached from 14 normal and nine AMD donors. RT-qPCR showed significant upregulation of RAGE, AGE R1, and AGE R3 in RPE cells overlying basal deposits compared to cells attached to morphologically normal Bruch's membrane. Immunohistochemical analysis for RAGE, AGER1, R2, and R3 showed diffuse, light staining of RPE cells and strong choriocapillaris staining in areas of normal Bruch's membrane. In areas of basal deposits, the RPE had more intense staining for RAGE and AGER1 compared to regions of normal Bruch's membrane. These results suggest that AGE receptors could influence the formation of basal deposits during aging and AMD.

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“…A cholesterolaccumulating sublayer of BrM is an apparent precursor to basal linear deposit, thought to provide a cleavage plane for dissecting choroidal vessels. 9,45 Therefore, cholesterol may play a role in promoting mechanical instability in ARM as well as atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein B in Cholesterol-Containing Drusen and Basal Deposits of Human Eyes with Age-Related Maculopathy

Malek

Guidry

et al. 2003

The American Journal of Pathology

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244

212

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Lipids accumulate in Bruch's membrane (BrM), a specialized vascular intima of the eye, and in extracellular lesions associated with aging and age-related maculopathy (ARM). We tested the hypothesis that ARM and atherosclerotic cardiovascular disease share molecules and mechanisms pertaining to extracellular lipid accumulation by localizing cholesterol and apolipoprotein B (apo B) in BrM, basal deposits, and drusen. Human donor eyes were preserved <4 hours postmortem and cryosectioned. Sections were stained with traditional lipid stains and filipin for esterified and unesterified cholesterol or probed with antibodies to apo B, apo E, and apo C-III. Normal adult retinal pigment epithelium (RPE) was subjected to RT-PCR and Western blot analysis for apolipoprotein mRNA and protein. Esterified and unesterified cholesterol was present in all drusen and basal deposits of ARM and normal eyes. Both apo B and apo E but not apo C-III were found in BrM, drusen, and basal deposits. Age-related maculopathy (ARM) is the leading cause of new, untreatable vision loss in the elderly in Western societies. [1][2][3] As shown in Figure 1A, ARM involves the retinal pigment epithelium (RPE, cells dedicated to sustaining photoreceptor health), the choriocapillaris (the blood supply to photoreceptors and the RPE), and Bruch's membrane (BrM, a thin vascular intima between the RPE and choriocapillaris). 4,5 Early ARM is characterized by moderate vision loss associated with characteristic extracellular lesions. Lesions between the RPE basal lamina and BrM can be focal (drusen) or diffuse (basal linear deposits). A diffuse lesion between the RPE and its basal lamina is basal laminar deposit. The term "sub-RPE deposits" is used for the combination of drusen and basal deposits and "basal deposits" for the combination of basal laminar deposit and basal linear deposit. Late ARM is characterized by severe vision loss associated with extensive RPE atrophy with or without the sequelae of choroidal neovascularization, ie, in-growth of choriocapillaries through BrM and under the RPE in the plane of drusen and basal linear deposits. Because the causes of ARM are obscure, recent studies have sought molecules present in the affected tissues and characteristic lesions to identify biochemical pathways perturbed by disease. 6 An important but incompletely characterized component of BrM and sub-RPE deposits is lipids. Normal BrM accumulates lipids with age, and the accumulation of esterified and unesterified cholesterol (EC and UC)-containing particles is especially prominent in the macula. 7-10 Drusen and basal deposits in aged eyes without ARM contain lipids, including cholesterol, 9 -13 and current evidence suggests that individual sub-RPE deposits are preferentially enriched in either neutral lipids or polar lipids. 13 The source of lipids and mechanisms of deposition are unknown. Analyses of BrM/ choroid lipid composition have implicated both local cells and plasma. 8,9 Atherosclerotic cardiovascular disease (CVD), the leading cause of death in Wester...

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Basal Linear Deposit and Large Drusen Are Specific for Early Age-Related Maculopathy

Cited by 338 publications

References 55 publications

Cigarette Smoke-Related Hydroquinone Induces Filamentous Actin Reorganization and Heat Shock Protein 27 Phosphorylation through p38 and Extracellular Signal-Regulated Kinase 1/2 in Retinal Pigment Epithelium

Cigarette Smoke-Related Hydroquinone Induces Filamentous Actin Reorganization and Heat Shock Protein 27 Phosphorylation through p38 and Extracellular Signal-Regulated Kinase 1/2 in Retinal Pigment Epithelium

The expression of advanced glycation endproduct receptors in rpe cells associated with basal deposits in human maculas

Apolipoprotein B in Cholesterol-Containing Drusen and Basal Deposits of Human Eyes with Age-Related Maculopathy

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