Characterization of β amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration

Anderson, Don H.; Talaga, K.C.; Rivest, Alexander J.; Barrón, Ernesto; Hageman, Gregory S.; Johnson, Lincoln V.

doi:10.1016/j.exer.2003.10.011

Cited by 297 publications

(265 citation statements)

References 49 publications

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“…Proposed mechanisms of AMD pathogenesis include chronic oxidative stress, ER stress, light damage, increased polyunsaturated fatty acids, abnormal phagocytosis, complement activation and inflammation [142][143][144][145][146][147][148][149][150][151][152]. In human RPE, induction of oxidative stress by H2O2 or photo-oxidation led to proteasome inhibition and accumulation of polyubiquitinated proteins and aggregates [152].…”

Section: Pdmentioning

confidence: 99%

“…Complement pathway dysregulation is thought to play a critical role in the formation of drusen [142,144,148]. An analysis of drusen components showed an abundance of regulatory proteins of the common complement pathway.…”

Section: Pdmentioning

confidence: 99%

“…In addition, RPE cells overlying drusen had increased cytoplasmic levels of complement inhibitors. Similar to T2DM and Alzheimer's disease, drusen consists of amyloid beta, a pro-inflammatory molecule that also activates complement [142] and the NLRP3 inflammasome [130,132]. Drusen components, complement C1q and oxidized lipids, activate the NLRP3 inflammasome resulting in increased production of the pro-inflammatory cytokines, IL-1 and IL-18 [156].…”

Section: Pdmentioning

confidence: 99%

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Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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Section: Pdmentioning

confidence: 99%

Section: Pdmentioning

confidence: 99%

Section: Pdmentioning

confidence: 99%

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Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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“…Extracellular deposits beneath the retinal pigment epithelium (RPE), known as drusen, are hallmarks of AMD and contain protein and lipid components capable of stimulating inflammation (Hageman et al, 2001;Mullins et al, 2000;Jiang et al, 2012). Amyloid-beta (Aβ), a peptide found in senile plaques in the brain in Alzheimer's disease (AD), is a constituent of drusen and is believed to contribute to the inflammatory state in the outer retina (Anderson et al, 2004;.…”

Section: Introductionmentioning

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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“…One of the initial sign of this disease is the presence of drusen in the macular area (6). Drusen plays an important role in the injury of retinal pigment epithelium by causing inflammatory modulator effects and later the development of CNV (7).…”

Section: Introductionmentioning

confidence: 99%

HLA B27 as Predisposition Factor to Suffer Age Related Macular Degeneration

et al. 2009

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To research whether specific alleles HLA class I (HLA-A and HLA-B) and class II (HLA-DR) are risk factors for the development of exudative type of Age Related Macular Degeneration (ARMD), HLA antigens are expressed both in normal and affected eyes with ARMD. We designed a prospective case-controlled study. We recruited 75 patients with choroidal neovascularization predominantly classic or occult, secondary to ARMD, and treated with photodynamic therapy. Two hundred and fifty patients over 55 years old, without ophthalmologic pathology who went to hospital for an analytical routine check were used as control. The analysis of the data shows a significant difference between two groups. Allele HLA-B27 correlated positively with ARMD (p < 0.0113). However, we didn't find alleles negatively associated. Thus HLA-B27 is an allele predisposed to suffer ARMD. Cellular & Molecular Immunology. 2009;6(4):303-307.

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Characterization of β amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration

Cited by 297 publications

References 49 publications

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

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

HLA B27 as Predisposition Factor to Suffer Age Related Macular Degeneration

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