Association between the RAGE G82S polymorphism and Alzheimer’s disease

Li, Keshen; Dai, Dawei; Zhao, Bin; Yao, Lifen; Yao, Songpo; Wang, Binyou; Yang, Ze

doi:10.1007/s00702-009-0334-6

Cited by 69 publications

(57 citation statements)

References 42 publications

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“…The G82S polymorphism of RAGE has important functional implications because it is associated with enhanced ligand binding, reduced sRAGE production, and consequently an enhanced receptor signaling (25)(26)(27)(28)(29). Nevertheless, it is not well understood how this RAGE polymorphism affects ligand binding and soluble RAGE production.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, this RAGE variant is associated with increased NF-B activation and inflammatory gene expression (25,26). In addition, the G82S polymorphism is associated with reduced levels of soluble RAGE (sRAGE) that in a number of diseases magnifies the contribution from RAGE toward inflammation (27)(28)(29)(30)(31). How ligand binding and sRAGE levels are altered by the G82S polymorphism is unknown.…”

mentioning

confidence: 99%

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The G82S Polymorphism Promotes Glycosylation of the Receptor for Advanced Glycation End Products (RAGE) at Asparagine 81

Park

Kleffmann

Hessian

2011

Journal of Biological Chemistry

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Interaction between the receptor for advanced glycation end products (RAGE) and its ligands amplifies the proinflammatory response. N-Linked glycosylation of RAGE plays an important role in the regulation of ligand binding. The receptor for advanced glycation end products (RAGE) 2 is a multiligand receptor that binds to carboxymethyl lysineand AGE-modified proteins and lipids but also to more autonomous ligands including high mobility group box 1 protein (HMGB1), members of the S100/Calgranulin protein family, amyloid ␤-peptide and Mac-1 (1-7). Binding of ligands to RAGE is mediated by an extracellular region of the receptor comprising an N-terminal variable (V)-domain and two constant (C)-immunoglobulin domains (2,8,9). Interaction between RAGE and ligands recruits diverse signal transduction pathways involving NF-B and MAP kinase activation and consequently the expression of proinflammatory genes (10 -14). RAGE also acts as an endothelial adhesion receptor promoting leukocyte recruitment during inflammation via a direct interaction with the ␤2-integrins Mac-1 or p150,95 expressed by leukocytes (15,16). RAGE contains two potential N-linked glycosylation sites at Asn 25 and Asn 81 (1). It is now well established that RAGE is N-link glycosylated and that some of the added N-glycan is further modified, resulting in an anionic nonsialylated carboxylated N-glycan (17-20). The nonsialylated carboxylated Nglycan is essential for binding of RAGE to HMGB1, S100A8/A9, and S100A12 in particular, indicating that N-linked glycosylation and/or the modification of the added N-glycan play important roles in the regulation of RAGE-ligand binding (18,21,22).A naturally occurring polymorphism has been identified that results in a glycine-to-serine substitution at position 82 within the V-domain. This polymorphism occurs with relatively high incidence compared with other RAGE polymorphisms that have been identified (23,24). The G82S mutant RAGE displays enhanced ligand binding to S100A12 and AGE ligands (25,26). Consequently, this RAGE variant is associated with increased NF-B activation and inflammatory gene expression (25,26). In addition, the G82S polymorphism is associated with reduced levels of soluble RAGE (sRAGE) that in a number of diseases magnifies the contribution from RAGE toward inflammation (27-31). How ligand binding and sRAGE levels are altered by the G82S polymorphism is unknown. The G82S substitution occurs within one of the potential N-linked glycosylation consensus sites, involving Asn 81 . On this basis, we hypothesized that the G82S substitution may influence the glycosylation pattern of RAGE, with consequences for ligand binding and proinflammatory signaling. Here, we describe detailed analysis of the glycosylation of RAGE and identify enhanced glycosylation induced by the G82S polymorphism.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The G82S Polymorphism Promotes Glycosylation of the Receptor for Advanced Glycation End Products (RAGE) at Asparagine 81

Park

Kleffmann

Hessian

2011

Journal of Biological Chemistry

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“…In AD patients, the plasma sRAGE levels are lower than in normal elderly and associated with cognitive deterioration (Li et al 2010), implicating that increasing the sRAGE levels by inducing mRAGE shedding might prevent the development of RAGE-mediated pathogenesis (Quade-Lyssy et al 2013). Furthermore, engagement of mRAGE with Ab activates several intracellular signaling pathways including mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-jB) signaling associated with oxidative stress and the release of several inflammatory factors such as interleukin-1beta (IL-1b), tumor necrosis factor-alpha (TNF-a), reactive oxygen species (ROS), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), plasminogen activator inhibitor-1 (PAI-1), and monocyte chemoattractant protein-1 (MCP-1), which are all involved in the progression of AD.…”

Section: Srage-ab Interactions: Inhibiting Ab Neurotoxicitymentioning

confidence: 96%

Role of RAGE in Alzheimer’s Disease

et al. 2015

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Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer's disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aβ depends on the balance between production and clearance. RAGE plays an important role in the Aβ clearance. RAGE acts as an important transporter via regulating influx of circulating Aβ into brain, whereas the efflux of brain-derived Aβ into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aβ generation via enhancing the activity of β- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE-Aβ interactions could inhibit Aβ neurotoxicity and promote Aβ clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aβ and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD.

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“…Indeed, it is known that certain single-nucleotide polymorphisms in the RAGE gene are associated with lower levels of plasma sRAGE in both health and disease [22,23]. In light of evidence that RAGE is a genetic determinant of pulmonary function (FEV1/FVC) [3], it will be important to determine whether genetic factors are predictors of sRAGE deficiency and neutrophilic-dominant inflammation in asthma and COPD.…”

Section: Mechanisms Of Lung Disease Mb Sukkar Et Almentioning

confidence: 99%

Soluble RAGE is deficient in neutrophilic asthma and COPD

Sukkar¹,

Wood²,

Tooze³

et al. 2011

Eur Respir J

130

112

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The receptor for advanced glycation end-products (RAGE) is a pattern-recognition receptor involved in the host response to injury, infection and inflammation. It is a membrane receptor, but also has soluble forms (sRAGE). Deficiencies in sRAGE are linked to heightened inflammation in various chronic conditions. We determined whether airway and systemic levels of sRAGE and the RAGE ligands HMGB1 (high-mobility group box-1) and serum amyloid A (SAA) are related to neutrophilic inflammation in asthma and chronic obstructive pulmonary disease (COPD).Bronchial lavage fluid from subjects with moderate-to-severe persistent asthma (n516) or COPD (n537), or from healthy controls (n518), was analysed for neutrophils, total sRAGE, endogenous secretory RAGE (esRAGE), HMGB1 and SAA. We also determined systemic levels of sRAGE in a separate group of asthmatic (n5101) and COPD (n534) subjects.Subjects with neutrophilic asthma or COPD had undetectable levels of lung sRAGE, while levels of sRAGE in asthma/COPD without neutrophilia were similar to those in controls. Systemic sRAGE was significantly decreased in subjects with neutrophilic asthma or COPD compared with those without airway neutrophilia. There was significant positive correlation between total sRAGE and esRAGE in the lung and systemically. HMGB1 levels were similar in all subject groups, while SAA was below detectable levels.Neutrophilic airway inflammation in asthma and COPD is associated with reduced sRAGE.

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Association between the RAGE G82S polymorphism and Alzheimer’s disease

Cited by 69 publications

References 42 publications

The G82S Polymorphism Promotes Glycosylation of the Receptor for Advanced Glycation End Products (RAGE) at Asparagine 81

The G82S Polymorphism Promotes Glycosylation of the Receptor for Advanced Glycation End Products (RAGE) at Asparagine 81

Role of RAGE in Alzheimer’s Disease

Soluble RAGE is deficient in neutrophilic asthma and COPD

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