The Complexity of Sporadic Alzheimer's Disease Pathogenesis: The Role of RAGE as Therapeutic Target to Promote Neuroprotection by Inhibiting Neurovascular Dysfunction

Alzheimer's disease (AD) is the most common cause of dementia. Amyloid plaques and neurofibrillary tangles are prominent pathological features of AD. Aging and age-dependent oxidative stress are the major nongenetic risk factors for AD. The beta-amyloid peptide (Aβ), the major component of plaques, and advanced glycation end products (AGEs) are key activators of plaque-associated cellular dysfunction. Aβ and AGEs bind to the receptor for AGEs (RAGE), which transmits the signal from RAGE via redox-sensitive pathways to nuclear factor kappa-B (NF-κB). RAGE-mediated signaling is an important contributor to neurodegeneration in AD. We will summarize the current knowledge and ongoing studies on RAGE function in AD. We will also present evidence for a novel pathway induced by RAGE in AD, which leads to the expression of thioredoxin interacting protein (TXNIP), providing further evidence that pharmacological inhibition of RAGE will promote neuroprotection by blocking neurovascular dysfunction in AD

RAGE and Alzheimer’s Disease: A Progression Factor for Amyloid-β-Induced Cellular Perturbation?

This is the publisher's version, also available electronically from http://iospress.metapress.com/content/d6621608n32478r2/?genre=article&issn=1387-2877&volume=16&issue=4&spage=833Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules which serves as a receptor for amyloid-β peptide (Aβ) on neurons, microglia, astrocytes, and cells of vessel wall. Increased expression of RAGE is observed in regions of the brain affected by Alzheimer's disease (AD), and Aβ-RAGE interaction in vitro leads to cell stress with the generation of reactive oxygen species and activation of downstream signaling mechanisms including the MAP kinase pathway. RAGE-mediated activation of p38 MAP kinase in neurons causes Aβ-induced inhibition of long-term potentiation in slices of entorhinal cortex. Increased expression of RAGE in an Aβ-rich environment, using transgenic mouse models, accelerates and accentuates pathologic, biochemical, and behavioral abnormalities compared with mice overexpressing only mutant amyloid-β protein precursor. Interception of Aβ interaction with RAGE, by infusion of soluble RAGE, decreases Aβ content and amyloid load, as well as improving learning/memory and synaptic function, in a murine transgenic model of Aβ accumulation. These data suggest that RAGE may be a therapeutic target for AD

Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products

BACKGROUND: Atherosclerosis is an inflammatory disease in which a perpetuated activation of NFkappaB via the RAGE (receptor for advanced glycation end products)-MAPK signalling pathway may play an important pathogenetic role. As recently S100 proteins have been identified as ligands of RAGE, we sought to determine the effects of the proinflammatory heterodimer of S100A8/S100A9 on the RAGE-NFkappaB mediated induction of proinflammatory gene expression. METHODS: Human umbilical vein endothelial cells (HUVEC) were preincubated for 72 h with AGE-albumin or unmodified albumin for control, whereas AGE-albumin induction resulted in an upregulation of RAGE. Following this preactivation, cells were stimulated for 48 h with heterodimeric human recombinant S100A8/S100A9. RESULTS: Heterodimeric S100A8/S100A9 enhanced secretion of IL-6, ICAM-1, VCAM-1 and MCP1 in AGE-albumin pretreated HUVEC in a dose dependent manner. These effects could not be detected after stimulation with the homodimeric proteins S100A8, S100A9, S100A1 and S100B. The effects of heterodimeric S100A8/S100A9 were reduced by inhibition of the MAP-kinase pathways ERK1/2 and p38 by PD 98059 and SB 203580, respectively. CONCLUSION: The heterodimeric S100A8/S100A9 might therefore play a hitherto unknown role in triggering atherosclerosis in diabetes and renal failure, pathophysiological entities associated with a high AGE burden. Thus, blocking heterodimeric S100A8/S100A9 might represent a novel therapeutic modality in treating atherosclerosis

The Pattern Recognition Receptor (RAGE) Is a Counterreceptor for Leukocyte Integrins: A Novel Pathway for Inflammatory Cell Recruitment

The pattern recognition receptor, RAGE (receptor for advanced glycation endproducts), propagates cellular dysfunction in several inflammatory disorders and diabetes. Here we show that RAGE functions as an endothelial adhesion receptor promoting leukocyte recruitment. In an animal model of thioglycollate-induced acute peritonitis, leukocyte recruitment was significantly impaired in RAGE-deficient mice as opposed to wild-type mice. In diabetic wild-type mice we observed enhanced leukocyte recruitment to the inflamed peritoneum as compared with nondiabetic wild-type mice; this phenomenon was attributed to RAGE as it was abrogated in the presence of soluble RAGE and was absent in diabetic RAGE-deficient mice. In vitro, RAGE-dependent leukocyte adhesion to endothelial cells was mediated by a direct interaction of RAGE with the β2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with β1-integrins. The RAGE–Mac-1 interaction was augmented by the proinflammatory RAGE-ligand, S100-protein. These results were corroborated by analysis of cells transfected with different heterodimeric β2-integrins, by using RAGE-transfected cells, and by using purified proteins. The RAGE–Mac-1 interaction defines a novel pathway of leukocyte recruitment relevant in inflammatory disorders associated with increased RAGE expression, such as in diabetes, and could provide the basis for the development of novel therapeutic applications

DAMP Signaling is a Key Pathway Inducing Immune Modulation after Brain Injury

Acute brain lesions induce profound alterations of the peripheral immune response comprising the opposing phenomena of early immune activation and subsequent immunosuppression. The mechanisms underlying this brain-immune signaling are largely unknown. We used animal models for experimental brain ischemia as a paradigm of acute brain lesions and additionally investigated a large cohort of stroke patients. We investigated the inflammatory potency of HMGB1 and its signaling pathways by immunological in vivo and in vitro techniques. Features of the complex behavioral sickness behavior syndrome were characterized by homecage behavior analysis. HMGB1 downstream signaling, particularly with RAGE, was studied in various transgenic animal models and by pharmacological blockade. Our results indicate that HMGB1 was released from the ischemic brain in the hyperacute phase of stroke in mice and patients. Cytokines secreted in the periphery in response to brain injury induced sickness behavior, which could be abrogated by inhibition of the HMGB1-RAGE pathway or direct cytokine neutralization. Subsequently, HMGB1-release induced bone marrow egress and splenic proliferation of bone marrow-derived suppressor cells, inhibiting the adaptive immune responses in vivo and vitro. Furthermore, HMGB1-RAGE signaling resulted in functional exhaustion of mature monocytes and lymphopenia, the hallmarks of immune suppression after extensive ischemia. This study introduces the HMGB1-RAGE-mediated pathway as a key mechanism explaining the complex postischemic brain-immune interactions

Receptor for advanced glycation endproducts (RAGE) deficiency protects against MPTP toxicity

Copyright © 2011 Elsevier Inc. All rights reserved.Peer reviewedPublisher PD

The effect of lifestyle intervention in obesity on the soluble form of activated leukocyte cell adhesion molecule

Background: The aim of this study was to investigate the effect of a lifestyle intervention in obesity on the soluble form of the activated leukocyte cell adhesion molecule (sALCAM) and its association with metabolic parameters. Methods: Twenty-nine obese subjects selected from the OPTIFAST®52 program. This program consisted into 2 crucial phases: an initial 12-week active weight reduction phase, followed by a 40-week weight maintenance phase. At baseline, after 12 weeks and at the end of the program, fasting glucose and insulin, total cholesterol, LDL-C, HDL-C, triglycerides, adiponectin, leptin, high sensitivity CRP, sALCAM, homeostasis model assessment-estimated insulin resistance (HOMA-IR) and leptin-to-adiponectin-ratio were determined. Oral glucose tolerance test (OGTT) was performed when indicated. Results: At baseline, the serum concentration of sALCAM was increased and correlated positively with HOMA-IR and negatively with age. At the end of the program, sALCAM concentrations decreased significantly. Multivariate analysis showed that sALCAM significantly correlated with age, glucose concentration after 2 h OGTT and the HOMA-IR. A higher decrease of HOMA-IR during the study was observed in subjects with higher concentration of sALCAM at baseline. Conclusions: sALCAM might be a novel biomarker in obesity that correlates and predicts insulin sensitivity improvement and that can be affected by lifestyle intervention

PLANNING OF HUMAN RESOURCE COMPETENCY DEVELOPMENT IN PT.XYZ WITH TAGUCHI METHOD

The problem of human resources is still a concern within the company to remain competitive in this globalization world. This shows that the problem of human resources greatly affect the implementation and success of the company in achieving goals and objectives. The company demand to obtain the development process and get quality human resources more urgent. And the development of human resource competence is necessary. This study uses experimental testing with several parameters of validity and reliability testing. For testing analysis using Taguchi Method. Based on the Response Table for Signal to Noise Ratios Nominal is best obtained taguchi test results obtained values obtained from the effect plot for means with the approach of table of means, then the intellectual competence is needed for the improvement of HR performance

Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response

This is the publisher's version, also available electronically from http://www.jci.org/articles/view/18704While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation