Inflammatory Mediators Induced by Amyloid-Beta in the Retina and RPE In Vivo: Implications for Inflammasome Activation in Age-Related Macular Degeneration

Liu, Ruozhou Tom; Gao, Jian; Cao, Siyang; Sandhu, Navroop; Cui, Jing; Chou, Chun Liang; Fang, Edward; Matsubara, Joanne A.

doi:10.1167/iovs.12-10849

Cited by 134 publications

(149 citation statements)

References 66 publications

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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). The NLRP3 inflammasome is an intracellular multi-protein complex that recruits and cleaves caspase-1 when activated; this inflammasome complex with activated caspase-1 in turn cleaves IL-1β and IL-18 pro-peptides into their mature forms (Halle et al, 2008;Martinon et al, 2002;Tarallo et al, 2012).…”

Section: Introductionmentioning

confidence: 80%

“…Anesthesia was induced with 5% halothane in 70/30 mixture of N 2 O and oxygen, and maintained with 1.5% halothane throughout surgical procedures. On Day 0, a single intraocular injection of Aβ 1-40 (7 μg) was performed on all animals according to described procedures (Liu et al, 2013). Treatment group received vinpocetine (n = 13) at a dosage of 15 mg/kg body weight, and control group received converted volume of DMSO (n = 13), as intraperitoneal (IP) injection 1 h prior to the intraocular injections, and then repeated daily for three subsequent days.…”

Section: Animal Treatment Studiesmentioning

confidence: 99%

“…Intraocular injection has been shown to effectively deliver Aβ peptide to the outer retina and RPE in earlier studies without the confounding effect of mechanical disturbances to the RPE layer due to subretinal delivery (Liu et al, 2013). Parenteral route for vinpocetine administration was chosen due to its good blood-brain (and hence blood-ocular) penetration, and poor oral bioavailability (Polgar et al, 1985).…”

Section: Nf-κb Activation Is Induced By Aβ and Suppressed By Vinpocetmentioning

confidence: 99%

“…The over-expression of pro-inflammatory cytokines generated by Aβ is not only present locally in the outer retina but also evident in the vitreous (Liu et al, 2013). Here we measured the effect of vinpocetine on secreted cytokines in the vitreous.…”

Section: Vinpocetine Led To Decreased Intravitreal Cytokine Concentramentioning

confidence: 99%

“…1997). TNF-α is upregulated by the RPE and retina in the presence of Aβ (Liu et al, 2013) and is capable of causing damage to photoreceptor cells (Nakazawa et al, 2011). Therefore, further investigation into the effect of NF-κB inhibition on the expression of inflammatory mediators is essential towards a better understanding of AMD pathogenesis and therapy.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 80%

Section: Animal Treatment Studiesmentioning

confidence: 99%

Section: Nf-κb Activation Is Induced By Aβ and Suppressed By Vinpocetmentioning

confidence: 99%

Section: Vinpocetine Led To Decreased Intravitreal Cytokine Concentramentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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Association of Anticholinergic Drug Use With Risk for Late Age-Related Macular Degeneration

et al. 2018

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IMPORTANCE Amyloid-β is a major component of retinal drusen, the primary lesions of age-related macular degeneration (AMD), and autopsy and animal models suggested that anticholinergic drug (ACD) use increased brain amyloid-β deposition. OBJECTIVE To investigate the association between exposure to ACDs and late AMD (features of neovascular AMD or geographic atrophy of the retinal pigment epithelium in at least 1 eye). DESIGN, SETTING AND PARTICIPANTS A multicenter case-control study in 4 French ophthalmologic centers comprising 200 cases with late AMD and 200 controls enrolled from July 2016 to June 2017. EXPOSURES Exposure to at least 3 months of ACDs started before AMD diagnosis was recorded during a specific interview. A dose-effect association with cumulative exposure duration and Anticholinergic Burden Score was explored. The association between ACD exposure and AMD was assessed by multivariate logistic regression analysis adjusted for age, sex, smoking status, family history of AMD, alcohol consumption, and use of anticoagulant and anti-inflammatory drugs. Odds ratios (ORs) and 95% confidence intervals were estimated. MAIN OUTCOMES AND MEASURES Association between exposure to ACDs and late AMD. RESULTS Among case participants, the mean (SD) age was 74.8 (9.2) years, 129 (64.5%) were women, 192 (96%) were white, 65 (32.5%) had geographic atrophy, 135 (67.5%) had neovascular AMD, 116 (58%) had unilateral AMD, and 84 (42%) had bilateral AMD. Among control participants, the mean (SD) age was 75.5 (7.2) years, with 116 (58%) women and 187 (93.5%) white participants. Twenty-six cases (13%) and 10 controls (5%) were exposed to ACDs throughout life for at least 3 months before AMD onset. Risk of AMD was increased with ever exposure to ACDs (adjusted OR [aOR], 2.84; 95% CI, 1.33-6.06; P = .007), high Anticholinergic Burden Score (Ն3) (aOR, 6.42; 95% CI, 1.38-29.92; P = .02), and longest cumulative exposure to ACD (Ն15 years) (aOR, 5.88; 95% CI, 1.22-28.31; P = .03). CONCLUSIONS AND RELEVANCE Risk of late AMD may be increased with at least 3 months' use of ACDs. A dose-effect association was suggested by a greater association with prolonged use and high Anticholinergic Burden Score. Further studies, in particular those with longitudinal design, are needed to confirm this association.

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Fat mass and obesity‐associated protein alleviates Aβ_1–40 induced retinal pigment epithelial cells degeneration via PKA/CREB signaling pathway

Chen

Wang

et al. 2022

Cell Biology International

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Amyloid‐β (Aβ) is thought to be a critical pathologic factor of retinal pigment epithelium (RPE) degeneration in age‐related macular degeneration (AMD). Aβ induces inflammatory responses in RPE cells and recent studies demonstrate the N6‐methyladenosine (m6A) regulatory role in RPE cell inflammation. m6A is a reversible epigenetic posttranslational modification, but its relationship with Aβ‐induced RPE degeneration is yet to be thoroughly investigated. The present study explored the role and mechanism of m6A in Aβ‐induced RPE degeneration model. This model was induced via intravitreally injecting oligomeric Aβ and the morphology of its retina was analyzed. One of m6A demethylases, the fat mass and obesity‐associated (FTO) gene expression, was assessed. An m6A‐messenger RNA (mRNA) epitranscriptomic microarray was employed for further bioinformatic analyses. It was confirmed that Aβ induced FTO upregulation within the RPE. Hypopigmentation alterations and structural disorganization were observed in Aβ‐treated eyes, and inhibition of FTO exacerbated retinal degeneration and RPE impairment. Moreover, the m6A‐mRNA epitranscriptomic microarray suggested that protein kinase A (PKA) was a target of FTO, and the PKA/cyclic AMP‐responsive element binding (CREB) signaling pathway was involved in Aβ‐induced RPE degeneration. m6A‐RNA binding protein immunoprecipitation confirmed that FTO demethylated PKA within the RPE cells of Aβ‐treated eyes. Altered expression of PKA and its downstream targets (CREB and brain‐derived neurotrophic factor) was confirmed by quantitative reverse‐transcription polymerase chain reaction and Western blot analyses. Hence, this study's findings shed light on FTO‐mediated m6A modification in Aβ‐induced RPE degeneration and indicate potential therapeutic targets for AMD.

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Inflammatory Mediators Induced by Amyloid-Beta in the Retina and RPE In Vivo: Implications for Inflammasome Activation in Age-Related Macular Degeneration

Cited by 134 publications

References 66 publications

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

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

Association of Anticholinergic Drug Use With Risk for Late Age-Related Macular Degeneration

Fat mass and obesity‐associated protein alleviates Aβ_1–40 induced retinal pigment epithelial cells degeneration via PKA/CREB signaling pathway

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Inflammatory Mediators Induced by Amyloid-Beta in the Retina and RPE In Vivo: Implications for Inflammasome Activation in Age-Related Macular Degeneration

Cited by 134 publications

References 66 publications

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

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

Association of Anticholinergic Drug Use With Risk for Late Age-Related Macular Degeneration

Fat mass and obesity‐associated protein alleviates Aβ1–40 induced retinal pigment epithelial cells degeneration via PKA/CREB signaling pathway

Contact Info

Product

Resources

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Fat mass and obesity‐associated protein alleviates Aβ_1–40 induced retinal pigment epithelial cells degeneration via PKA/CREB signaling pathway