Amyloid‐β(1‐42) alters structure and function of retinal pigmented epithelial cells

Bruban, Julien; Glotin, Anne-Lise; Dinet, Virginie; Chalour, Naima; Sennlaub, Florian; Jonet, Laurent; An, Ning; Faussat, Anne Marie; Mascarelli, Frédéric

doi:10.1111/j.1474-9726.2009.00456.x

Cited by 104 publications

(103 citation statements)

References 45 publications

(62 reference statements)

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“…Injection of oligomeric amyloid β peptide into the subretinal space of B6 mice causes RPE hypertrophy and hypopigmentation (but not apoptosis) and diminished expression of RLBP1, RPE65, and tight junction proteins (74). Mice homozygous for a null mutation in the hemochromatosisassociated gene, Hfe, exhibit late-onset (18 months) RPE hypertrophy and hyperplasia, presumably as a result of iron accumulation (75).…”

Section: Discussionmentioning

confidence: 99%

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

Zhao

Yasumura²,

Li³

et al. 2011

J. Clin. Invest.

272

285

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Retinal pigment epithelial (RPE) cell dysfunction plays a central role in various retinal degenerative diseases, but knowledge is limited regarding the pathways responsible for adult RPE stress responses in vivo. RPE mitochondrial dysfunction has been implicated in the pathogenesis of several forms of retinal degeneration. Here we have shown that postnatal ablation of RPE mitochondrial oxidative phosphorylation in mice triggers gradual epithelium dedifferentiation, typified by reduction of RPE-characteristic proteins and cellular hypertrophy. The electrical response of the retina to light decreased and photoreceptors eventually degenerated. Abnormal RPE cell behavior was associated with increased glycolysis and activation of, and dependence upon, the hepatocyte growth factor/met proto-oncogene pathway. RPE dedifferentiation and hypertrophy arose through stimulation of the AKT/mammalian target of rapamycin (AKT/mTOR) pathway. Administration of an oxidant to wild-type mice also caused RPE dedifferentiation and mTOR activation. Importantly, treatment with the mTOR inhibitor rapamycin blunted key aspects of dedifferentiation and preserved photoreceptor function for both insults. These results reveal an in vivo response of the mature RPE to diverse stressors that prolongs RPE cell survival at the expense of epithelial attributes and photoreceptor function. Our findings provide a rationale for mTOR pathway inhibition as a therapeutic strategy for retinal degenerative diseases involving RPE stress. IntroductionThe retinal pigment epithelium (RPE) is a polarized, cuboidal epithelial cell layer situated in the outer retina between the photoreceptors and choroidal vasculature. The RPE supplies an estimated 60% of the glucose consumed by the neural retina (1) and performs a variety of other functions crucial for retinal homeostasis, including delivery of amino acids and docosahexaenoic acid for photoreceptor protein and membrane synthesis; transport, storage, and enzymatic conversion of retinoids essential for phototransduction; regulation of fluid and ion balance in the subretinal space; maintenance of the blood retinal barrier; secretion of growth factors; and phagocytosis of shed photoreceptor outer segment membranes (2). The RPE is a postmitotic tissue, so RPE cells must carry out these functions for the life of an individual.The retinal degenerative consequences of mutations in RPEexpressed genes illustrate the importance of the RPE for photoreceptor viability in humans. Mutations that impair production of the chromophore 11-cis retinal cause Leber congenital amaurosis, retinitis pigmentosa (RP), and allied disorders (3). Disruption of RPE phagocytosis causes RP and rod/cone dystrophy (4, 5). Mutations that affect ion channel function cause disease of the specialized retinal region necessary for high-acuity vision (the macula) (6) as well as RP (7), while mutations in genes encoding the RPE-secreted proteins TIMP3 (8) and EFEMP1 (9) cause lateronset macular disease.

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Section: Discussionmentioning

confidence: 99%

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

Zhao

Yasumura²,

Li³

et al. 2011

J. Clin. Invest.

272

285

View full text Add to dashboard Cite

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“…Aβ is a known activator of the complement system (37,38,66,67) and has toxic effects on RPE cells (68). Oligomeric, protofibrillar, and mature fibrillar forms of Aβ have been detected in drusen using conformation-specific antibodies (40,41) and classic amyloid stains like thioflavin T and Congo red (35,37).…”

Section: Discussionmentioning

confidence: 99%

Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration

Ding

Johnson²,

Herrmann³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

173

164

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Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. Amyloid β (Aβ) peptides, Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), have been implicated previously in the AMD disease process. Consistent with a pathogenic role for Aβ, we show here that a mouse model of AMD that invokes multiple factors that are known to modify AMD risk (aged human apolipoprotein E 4 targeted replacement mice on a high-fat, cholesterolenriched diet) presents with Aβ-containing deposits basal to the retinal pigmented epithelium (RPE), histopathologic changes in the RPE, and a deficit in scotopic electroretinographic response, which is reflective of impaired visual function. Strikingly, these electroretinographic deficits are abrogated in a dose-dependent manner by systemic administration of an antibody targeting the C termini of Aβ40 and Aβ42. Concomitant reduction in the levels of Aβ and activated complement components in sub-RPE deposits and structural preservation of the RPE are associated with anti-Aβ40/42 antibody immunotherapy and visual protection. These observations are consistent with the reduction in amyloid plaques and improvement of cognitive function in mouse models of Alzheimer's disease treated with anti-Aβ antibodies. They also implicate Aβ in the pathogenesis of AMD and identify Aβ as a viable therapeutic target for its treatment.A ge-related macular degeneration (AMD) affects about 30% of Americans over 70 y of age (1-3) and is the leading cause of irreversible blindness in the Western world (4). It is a progressive retinal degenerative disease influenced by both environmental and genetic factors. Although the presence of a few small hard drusen is a normal, nonvision-impairing part of aging, the deposition of large diffuse drusen in the macula adversely impacts vision and is indicative of early AMD. As AMD progresses to late-stage disease, it is categorized as either dry [geographic atrophy with photoreceptor loss and extensive atrophy of the retinal pigmented epithelium (RPE)] or wet [exudative with subsequent choroidal neovascularization (CNV)] (5). Currently, there are no effective treatments for early AMD, and treatments for late-stage disease are limited to photodynamic therapy, macular translocation, and antivascular endothelial growth factor drugs (6-9).The strongest known risk factors are advanced age and cigarette smoking, with additional risk conferred by body mass index and diets high in fat (1,(10)(11)(12)(13)(14). The last decade has also yielded strong evidence that genotype, especially for genes involved in inflammation and the innate immune system, influences AMD risk and progression. Genes implicated as risk factors include complement factor H (CFH) (15-18), complement factor B (19), complement C3 (20), apolipoprotein E (APOE) (21-25), toll-like receptor 4 (26), LOC387715/ARMS2 (27, 28), HTRA1 (29, 30), ABCA4 (31), and fibulin 5 (32). Additional support for a role for chronic local inflammation in AMD comes from the discovery that protein components of drusen include activated co...

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“…To investigate the effects of Ab(1-42) on the retina, mice were anesthetized with sodium pentobarbital (5 mg ⁄ 100 g) and underwent a single unilateral subretinal injection with Ab peptide (1.25 nmol ⁄ 2 lL) in PBS, as previously described (Bruban et al, 2009(Bruban et al, , 2011. Fluorescein isothiocyanate (FITC)-conjugated Ab(1-42) and its inactive reverse control peptide, Ab(42-1), were supplied by Bachem (Weil am Rhein, Germany).…”

Section: Experimental Procedures Animals and Animal Treatmentmentioning

confidence: 99%

“…The accumulation of Ab in the subretinal space might contribute to the 25-30% reduction in photoreceptors that occurs over human lifetimes (Curcio et al, 1993). We have showed that subretinal injection of Ab(1-42) damages the RPE in young and old mice (Bruban et al, 2009): photoreceptors die by apoptosis within a few days and microglial cells phagocytize photoreceptor debris and Ab after subretinal injection of Ab(1-42) (Bruban et al, 2011). Anti-Ab antibody immunotherapy has recently been shown to protect against RPE damage and vision loss in a mouse model of age-related macular degeneration (Ding et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Distinct effects of inflammation on gliosis, osmohomeostasis, and vascular integrity during amyloid beta‐induced retinal degeneration

et al. 2012

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SummaryIn normal retinas, amyloid-b (Ab) accumulates in the subretinal space, at the interface of the retinal pigment epithelium, and the photoreceptor outer segments. However, the molecular and cellular effects of subretinal Ab remain inadequately elucidated. We previously showed that subretinal injection of Ab(1-42) induces retinal inflammation, followed by photoreceptor cell death. The retinal Mü ller glial (RMG) cells, which are the principal retinal glial cells, are metabolically coupled to photoreceptors. Their role in the maintenance of retinal water ⁄ potassium and glutamate homeostasis makes them important players in photoreceptor survival. This study investigated the effects of subretinal Ab(1-42) on RMG cells and of Ab(1-42)-induced inflammation on retinal homeostasis. RMG cell gliosis (upregulation of GFAP, vimentin, and nestin) on day 1 postinjection and a proinflammatory phenotype were the first signs of retinal alteration induced by Ab(1-42). On day 3, we detected modifications in the protein expression patterns of cyclooxygenase 2 (COX-2), glutamine synthetase (GS), Kir4.1 [the inwardly rectifying potassium (Kir) channel], and aquaporin (AQP)-4 water channels in RMG cells and of the photoreceptor-associated AQP-1. The integrity of the blood-retina barrier was compromised and retinal edema developed. Ab(1-42) induced endoplasmic reticulum stress associated with sustained upregulation of the proapoptotic factors of the unfolded protein response and persistent photoreceptor apoptosis. Indomethacin treatment decreased inflammation and reversed the Ab(1-42)-induced gliosis and modifications in the expression patterns of COX-2, Kir4.1, and AQP-1, but not of AQP-4 or GS. Nor did it improve edema. Our study pinpoints the adaptive response to Ab of specific RMG cell functions.

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Amyloid‐β(1‐42) alters structure and function of retinal pigmented epithelial cells

Cited by 104 publications

References 45 publications

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration

Distinct effects of inflammation on gliosis, osmohomeostasis, and vascular integrity during amyloid beta‐induced retinal degeneration

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