Microarray Analysis Identifies Changes in Inflammatory Gene Expression in Response to Amyloid-β Stimulation of Cultured Human Retinal Pigment Epithelial Cells

Kurji, Khaliq; Cui, Jing; Lin, Tony; Harriman, David; Prasad, Shiv S.; Kojic, Ljuba; Matsubara, Joanne A.

doi:10.1167/iovs.09-3622

Cited by 75 publications

(94 citation statements)

References 83 publications

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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.

176

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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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.

176

164

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“…A microarray identified the production of Il-1b and Il-8 as the main response to Ab(1-40) of RPE cells in culture (Kurji et al, 2010). Therefore, RPE may be a major source of inflammation after Ab injection.…”

Section: Role Of Inflammation In the Subretinal Ab-induced Rmg Cell Gmentioning

confidence: 99%

“…Therefore, RPE may be a major source of inflammation after Ab injection. The RPE may also play a role in the migration of microglial cells to the subretinal space of Ab(1-42)-injected mice, because Ab(1-40) stimulates the production of CCL2 and Il-8, by RPE cells in culture (Wang et al, 2009;Kurji et al, 2010). This might suggest that microglial cells are recruited by CCL2 and ⁄ or Il-8 produced by RPE cells.…”

Section: Role Of Inflammation In the Subretinal Ab-induced Rmg Cell Gmentioning

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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“…Aβ 1-40 activates inflammatory/immune response pathways but not acute toxicity in RPE cells, in keeping with the insidious onset of AMD (Kurji et al, 2010). More recently, the pro-inflammatory effect of Aβ 1-40 was verified in vivo using an intravitreal injection model that demonstrated upregulation of NLR family, pyrin domain containing 3 (NLRP3) inflammasome associated products (interleukin 1 beta (IL-1β), IL-18), cytokines (IL-6, tumor necrosis factor alpha (TNF-α)), and increased microglia activation (Liu et al, 2013).…”

Section: Introductionmentioning

confidence: 85%

“…Aβ 1-40 oligomeric peptide (American Peptide, Sunnyvale CA) was prepared according to previously described methods (Kurji et al, 2010) and stored in 1.4 μg/μL aliquots. Vinpocetine (67358-1G) was purchased from AK Scientific Inc (Union City CA).…”

Section: Peptide and Vinpocetine Preparationmentioning

confidence: 99%

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

Liu

Wang

et al. 2014

Experimental Eye Research

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Chronic inflammation is a key pathogenic process in age-related macular degeneration (AMD). Amyloid-beta (Aβ) is a constituent of AMD drusen and promotes the activation of NLRP3 inflammasome which facilitates the production of cytokines. We investigated the role of transcription factor NF-κB in the activation of inflammasome in the RPE and the effect of vinpocetine, a dietary supplement with inhibitory effect on NF-κB. ARPE19/NF-κB-luciferase reporter cells treated with Aβ demonstrated enhanced NF-κB activation that was significantly suppressed by vinpocetine. Intraperitoneal injection of vinpocetine (15 mg/kg) inhibited NF-κB nuclear translocation and reduced the expression and activation of NLRP3, caspase-1, IL-1β, IL-18, and TNF-α in the RPE of adult rats that received intraocular Aβ, as measured by retinal immunohistochemistry and Western blot. Cytokine level in the vitreous was assayed using multiplex suspension arrays and revealed significantly lower concentration of MIP-3α, IL-6, IL-1α, IL-1β, IL-18, and TNF-α in vinpocetine treated animals. These results suggest that the NF-κB pathway is activated by Aβ in the RPE and signals the priming of NLRP3 inflammasome and the expression of pro-inflammatory cytokines including the inflammasome substrates IL-1β and IL-18. NF-κB inhibition may be an effective approach to stem the chronic inflammatory milieu that underlies the development of AMD. Vinpocetine is a potentially useful anti-inflammatory agent that is well-tolerated in long term use.

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Microarray Analysis Identifies Changes in Inflammatory Gene Expression in Response to Amyloid-β Stimulation of Cultured Human Retinal Pigment Epithelial Cells

Abstract: Abeta(1-40) promotes RPE gene expression changes in pathways associated with immune response, inflammation, and cytokine and interferon signaling pathways. Results may relate to in vivo mechanisms associated with the pathogenesis of AMD.

Cited by 75 publications

References 83 publications

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

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

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

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