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PubMed2005

RAGE: a journey from the complications of diabetes to disorders of the nervous system - striking a fine balance between injury and repair.

The Receptor for Advanced Glycation End Products (RAGE) is a multiligand member of the immunoglobulin superfamily. RAGE interacts with AGEs, the products of nonenzymatic glycation/oxidation of proteins and lipids that accumulate in diverse settings, such as diabetes, inflammation, renal failure, pro-oxidant states and natural aging. In addition, RAGE is also a receptor for amyloid-beta peptide and beta-sheet fibril species. Recent studies underscore the premise that RAGE interacts with pro-inflammatory molecules, including S100/calgranulins and amphoterin, the latter also known as high mobility group box 1 (HMGB1). In chronic neurodegenerative disorders as well as in nerve tissue upon acute injury, evidence points to upregulation of both RAGE and these ligand families. In this review, we will discuss the implications of transient/self-limited upregulation of RAGE and its ligands, vs sustained/chronic upregulation of this axis in neurodegeneration vs repair in both the central and peripheral nervous systems. Experimental evidence supports the premise that RAGE bears both homeostatic and injurious properties in the nervous system, thereby highlighting "yin/yang" features of this receptor and its ligand families.

Animals↗
PubMed2006

The neurobiology of aggression and rage: role of cytokines.

Recent studies have suggested an important relationship linking cytokines, immunity and aggressive behavior. Clinical reports describe increasing levels of hostility, anger, and irritability in patients who receive cytokine immunotherapy, and there are reports of a positive correlation between cytokine levels and aggressive behavior in non-patient populations. On the basis of these reports and others describing the presence or actions of different cytokines in regions of the brain associated with aggressive behavior, our laboratory embarked upon a program of research designed to identify and characterize the role of IL-1 and IL-2 in the hypothalamus and midbrain periaqueductal gray (PAG)--two regions functionally linked through reciprocal anatomical connections--in the regulation of feline defensive rage. A paradigm involved cytokine microinjections into either medial hypothalamus and elicitation of defensive rage behavior from the PAG or vice versa. These studies have revealed that both cytokines have potent effects in modulating defensive rage behavior. With respect to IL-1, this cytokine facilitates defensive rage when microinjected into either the medial hypothalamus or PAG and these potentiating effects are mediated through 5-HT2 receptors. In contrast, the effects of IL-2 are dependent upon the anatomical locus. IL-2 microinjected into the medial hypothalamus suppresses defensive rage and this suppression is mediated through GABA(A) receptors, while microinjections of IL-2 in the PAG potentiate defensive rage, in which these effects are mediated through NK-1 receptors. Present research is designed to further delineate the roles of cytokines in aggressive behavior and to begin to unravel the possible signaling pathways involved this process.

Aggression↗
PubMed2005

Sleep disturbance and rage attacks in opsoclonus-myoclonus syndrome: response to trazodone.

OBJECTIVES: Parents of children with opsoclonus-myoclonus syndrome (OMS) frequently describe poor sleep and rage attacks. We hypothesized that these manifestations are related and could result from underlying monoaminergic dysfunction. STUDY DESIGN: We clinically characterized the sleep and behavioral characteristics of 51 young children with OMS; 19 of those with the most disruptive sleep patterns were treated with trazodone, a soporific serotonergic agent. RESULTS: Sleep disturbances, including prolonged sleep latency, fragmented sleep, reduced quantity of sleep, snoring, and non-restorative sleep, were reported in 32 children, and frequent rage attacks were reported in 25. In 59% of the poor sleepers, parents felt that the problem was severe enough to warrant treatment. Children sleeping <10 hours/night had a higher rage frequency than those who slept more. Of the children who required trazodone, 84% were receiving corticosteroids or adrenocorticotropic hormone (corticotrophin), compared with 37% in the subgroup with normal sleep. Trazodone (3.0 +/- 0.4 mg/kg/day) improved sleep and behavior in 95% of the children, significantly increasing total sleep time by 72%, decreasing the number of awakenings by 76%, and reducing rage attacks by 33%. CONCLUSIONS: Children with OMS exhibited multiple types of sleep disturbances, which contributed to rage attacks. Trazodone was effective in improving sleep and decreasing rage attacks and was well tolerated, even in toddlers.

Adolescent↗
PubMed1997

Neurotransmitters regulating defensive rage behavior in the cat.

This review summarizes recent findings of our laboratory that have been directed at: (1) identifying the neural circuits underlying the expression and modulation of defensive rage behavior in the cat and the neurotransmitters associated with these pathways; and (2) determining which components of the circuitry are affected by alcohol administration and which significantly alter the rage mechanism. The experiments described herein incorporated a number of converging methods, which include brain stimulation, behavioral pharmacology, immunocytochemistry, retrograde tract tracing and receptor binding. For behavioral pharmacological studies, monopolar electrodes and cannula-electrodes were implanted into selected regions along the limbic-midbrain axis for electrical stimulation and local microinfusion of drugs. The findings demonstrated: (1) a direct pathway from the anterior medial hypothalamus to the dorsal periaqueductal gray (PAG) over which this response is mediated. This pathway utilizes excitatory amino acids that act upon NMDA receptors within the midbrain PAG; (2) that the region of the dorsal PAG, from which defensive rage could be elicited, receives other inputs from the basal amygdala that facilitate this response by acting upon NMDA receptors; (3) a pathway from the medial amygdala to the medial hypothalamus that also facilitates defensive rage and whose functions are mediated by substance P receptors within the medial hypothalamus; (4) that the PAG also receives enkephalinergic inputs from the central nucleus of amygdala, which act upon mu receptors, and which powerfully suppress defensive rage; and (5) that recent findings reveal that ethanol administration facilitates defensive rage by virtue of its interactions with the medial hypothalamus, its descending projection to the PAG, and possibly with NMDA receptors within this pathway.

Aggression↗
PubMed1996

Differential effects of ethanol on feline rage and predatory attack behavior: an underlying neural mechanism.

Previous studies have shown that, at certain dose levels, ethanol can exert a powerful, facilitatory effect on aggressive behavior in both animals and humans. In the cat, however, it was discovered that ethanol differentially alters two forms of aggression that are common to this species. Defensive rage behavior is significantly enhanced, whereas predatory attack behavior is suppressed by ethanol administration. One possible mechanism governing alcohol's potentiation of defensive rage behavior is that it acts on the descending pathway from the medial hypothalamus to the midbrain periaqueductal gray (PAG)-an essential pathway for the expression of defensive rage behavior that uses excitatory amino acids as a neurotransmitter. This hypothesis is supported by the finding that the excitatory effects of alcohol on defensive rage behavior are blocked by administration of the N-methyl-D-aspartate antagonist alpha-2-amino-7-phosphoheptanoic acid (AP-7) when microinjected into the periaqueductal gray, a primary neuronal target of descending fibers from the medial hypothalamus that mediate the expression of defensive rage behavior. Thus, the present study establishes for the first time a specific component of the neural circuit for defensive rage behavior over which the potentiating effects of ethanol are mediated.

Aggression↗
PubMed2001

Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells.

Advanced glycation end-product (AGE) is important in the pathogenesis of diabetic nephropathy (DN), and captopril (an angiotensin converting enzyme inhibitor) is effective in treating this disorder. We have shown that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) cascade is responsible for AGE-induced mitogenesis in NRK-49F (normal rat kidney fibroblast) cells, but its role in renal fibrosis in DN remains unknown. Therefore, we have sought to determine whether JAK/STAT is involved in AGE-regulated collagen production in NRK-49F cells. We found that AGE time (1-7 days) and dose (10-200 microg/ml)-dependently increased collagen production in these cells. Additionally, AGE increased RAGE (receptor for AGE) protein expression. AGE-induced RAGE expression was dose-dependently inhibited by antisense RAGE oligodeoxynucleotide (ODN) and captopril. AGE-induced type I collagen production and JAK2-STAT1/STAT3 activation were decreased by AG-490 (a specific JAK2 inhibitor), antisense RAGE ODN and captopril. Meanwhile, STAT1 and STAT3 decoy ODNs also suppressed the induction of collagen by AGE. We concluded that RAGE and the JAK2-STAT1/STAT3 pathway were involved in AGE-induced collagen production in NRK-49F cells. Furthermore, captopril was found to reverse AGE-induced collagen production, probably by attenuating RAGE expression and JAK2-STAT1/STAT3 activities.

Base Sequence↗
PubMed2005

Generation of RAGE-1 and MAGE-9 peptide-specific cytotoxic T-lymphocyte lines for transfer in patients with renal cell carcinoma.

Renal cell carcinomas (RCCs) are supposed to be immunogenic, and several clinical trials of immunotherapy using tumor lysate-pulsed dendritic cells (DCs) have been performed. We report on the generation of RAGE-1 and MAGE-9 peptide-specific CTL lines. RAGE-1 and MAGE-9 are expressed in 56% and 38% of RCCs. Seven MAGE-9- and 13 RAGE-1-derived peptides were found to be immunogenic in the context of the HLA-A*0201 MHC. CTLs were generated by coculture with peptide-pulsed, activated B cells, which were easily generated in great quantities and displayed functional activity for a prolonged period of time. MAGE-9 and RAGE-1 peptide-specific CTL lines were strictly peptide-specific and displayed high cytotoxic activity not only against peptide-loaded T2 cells but also against HLA-A*0201-positive RCC lines, which naturally express MAGE-9, RAGE-1 or both. Thus, B cells are well suited as APCs for the generation of large numbers of tumor peptide-specific CTLs for adoptive transfer. MAGE-9 as well as RAGE-1 may well provide suitable targets for immunotherapy of RCC.

Adoptive Transfer↗
PubMed2004

Receptor for advanced glycation endproduct (RAGE)-mediated nuclear factor-kappaB activation in vasculitic neuropathy.

Binding of ligands to the receptor for advanced glycation endproducts (RAGE) results in activation of the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) and subsequent expression of NF-kappaB-regulated cytokines. In order to determine whether engagement of RAGE contributes to the pathogenesis of vasculitic neuropathy, we studied the presence of the RAGE ligand N(epsilon)-(carboxymethyl)lysine (CML), the receptor itself, NF-kappaB, and interleukin-6 (IL-6) in sural nerve biopsies of 12 patients with vasculitic neuropathies and 12 controls. In the patients, CML, RAGE, NF-kappaB, and IL-6 were localized in mononuclear cells, epineurial and endoneurial vessels and the perineurium. CML, RAGE, NF-kappaB, and IL-6 were expressed by CD4(+), CD8(+), and CD68(+) cells invading the nerves. Controls showed only weak staining. These data suggest that the RAGE pathway plays a critical proinflammatory role in vasculitic neuropathy.

Adult↗
PubMed1997

Beta amyloid toxicity does not require RAGE protein.

It has been suggested that a receptor for advanced glycation end products (RAGE) is the nerve cell receptor for amyloid beta protein (A beta). To determine if this is indeed the case, two neural cell lines as well as rat cortical neurons were examined for the presence of the mRNA for RAGE by PCR and northern blot analysis. Although lung was strongly positive, in no case was RAGE mRNA detected in the cultured neural cells. Glycated-albumin is a major ligand for RAGE and the cell surface RAGE protein is trypsin sensitive. In agreement with the mRNA data, trypsin treatment did not alter A beta toxicity, nor did glycated albumin modify the A beta response. It follows that RAGE is not the neural receptor for A beta.

Amyloid beta-Peptides↗
PubMed1996

Clinical usefulness of contrast-enhanced MP-RAGE of the brain.

Our purpose was to evaluate the usefulness of a 3D T1-weighted gradient-echo sequence (MP-RAGE) in clinical practice. We prospectively examined 200 patients with a variety of neurological disorders and symptoms. We compared lesion conspicuity and contrast enhancement on MP-RAGE images with conventional gadolinium-enhanced spin-echo (SE) T1-weighted images. Both the original MP-RAGE data and the reformatted images were characterised by improved differentiation between grey and white matter. More lesions were found on the 3D series, in both patients with neoplastic and non-neoplastic disease. Contrast enhancement of small oedematous lesions affecting the white matter in demyelinating disease was less obvious. Multiplanar reformatting, which can be realised in any desired plane and surface rendering with sophisticated segmentation algorithms superbly displayed the underlying anatomical relationships between lesions and normal brain structures. Excellent spatial resolution, the absence of posterior fossa artefacts and equivalent contrast enhancement resulted in an increased number of space-occupying lesions being found on the MP-RAGE images. Thus contrast-enhanced MP-RAGE is an alternative to conventional SE imaging in the investigation of intracranial masses. Although the total number of lesions found in patients with demyelinating disease was significantly higher on MP-RAGE, demonstration of blood-brain-barrier breakdown in active lesions was less obvious.

Adult↗
PubMed2005

The RAGE Gly82Ser polymorphism is not associated with cardiovascular disease in the Framingham offspring study.

The receptor for advanced glycation end-products (RAGE) is expressed to enhance degrees in human atherosclerotic plaques and co-localizes with inflammatory and pro-oxidant mediators in the vulnerable regions of the plaque. Previous studies highlighted a number of variants in the gene encoding the receptor, including a Gly to Ser substitution at amino acid 82 within the ligand-binding domain of RAGE. The Ser82 allele enhanced ligand-binding affinity and increased ligand-stimulated generation of inflammatory mediators in transfected cells and human monocytes compared to the common RAGE Gly82 allele. Thus it was logical to test the hypothesis that increased prevalence of the Gly82Ser polymorphism was associated with cardiovascular events in the Framingham offspring study (n=1632). Our analyses revealed that the Gly82Ser RAGE polymorphism did not demonstrate any association with the incidence of cardiovascular disease in diabetic or non-diabetic subjects (Gly82 96%, Ser82 4%). Analysis of specific manifestations of cardiovascular disease, including coronary heart disease (CHD), cardiovascular disease (CVD), myocardial infarction (MI) and ischemic disease (ISD) revealed no association with RAGE genotype. Further studies are required on other more prevalent genetic variants of RAGE and cardiovascular disease.

Aged↗
PubMed2005

RAGE and amyloid beta interactions: atomic force microscopy and molecular modeling.

In the AD brain, there are elevated amounts of soluble and insoluble Abeta peptides which enhance the expression of membrane bound and soluble receptor for advanced glycation end products (RAGE). The binding of soluble Abeta to soluble RAGE inhibits further aggregation of Abeta peptides, while membrane bound RAGE-Abeta interactions elicit activation of the NF-kappaB transcription factor promoting sustained chronic neuroinflammation. Atomic force microscopy observations demonstrated that the N-terminal domain of RAGE, by interacting with Abeta, is a powerful inhibitor of Abeta polymerization even at prolonged periods of incubation. Hence, the potential RAGE-Abeta structural interactions were further explored utilizing a series of computational chemistry algorithms. Our modeling suggests that a soluble dimeric RAGE assembly creates a positively charged well into which the negative charges of the N-terminal domain of dimeric Abeta dock.

Alzheimer Disease↗
PubMed2004

RAGE (receptor for advanced glycation end products): a central player in the inflammatory response.

The present review focuses on the role of RAGE, the "receptor for advanced glycation end products", in the inflammatory response. RAGE is a multiligand receptor that propagates cellular dysfunction in several inflammatory disorders, in tumors and in diabetes. RAGE is expressed at low levels in normal tissues, but becomes upregulated at sites where its ligands accumulate. RAGE may play a dual role in the inflammatory response: (i) interaction of RAGE on leukocytes or endothelial cells (ECs) with its ligands results in cellular activation involving the transcription factor NF-kappaB; (ii) on the other hand, RAGE on ECs may function as an adhesive receptor that directly interacts with leukocyte ss2-integrins, thereby directly being involved in inflammatory cell recruitment. These different aspects are discussed in the present review.

Animals↗
PubMed2004

Autoimmunity in Alzheimer's disease: increased levels of circulating IgGs binding Abeta and RAGE peptides.

Plasma samples derived from 33 Alzheimer's disease (AD) and 42 control participants were subjected to several steps to purify specific anti-(amyloid)Abeta IgGs. Affinity-purified IgGs binding the peptide Abeta1-42, a neurotoxic sequence derived from the trans-membrane amyloid precursor protein, exhibited nearly four-fold higher titers in AD patients compared with their control non-AD cohort. Affinity-purified IgGs binding a fragment of the receptor for advanced glycation end products (RAGE) likewise were increased nearly three-fold in AD individuals. Abeta and RAGE IgG titers were negatively correlated with cognitive status, i.e. the more cognitively impaired individuals tended to exhibit higher IgG titers. Abeta IgG titers were negatively correlated with age in the control group, but not with the AD group. Levels of circulating AB- and RAGE-like proteins were not different between AD and control participants, nor was there a relationship between individual IgG titers and the respective Abeta- and RAGE-like proteins. Freshly prepared leukocyte preparations were subjected to flow cytometric analysis. AD individuals exhibited significantly increased populations of cells expressing binding sites for monoclonal antibodies directed against Abeta (5.5-fold), betaAPP (3.5-fold), and RAGE (2.6-fold) relative to the control group. These findings confirm the presence of circulating IgGs specifically directed at proteins implicated in immunological processes linked to AD. The close relationship between titers for Abeta and RAGE IgGs suggests the possibility that the antibodies are being produced in response to a common mechanism or protein complex (with the respective epitopes) linked to the disease.

Adult↗
PubMed2003

RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy.

Diabetic nephropathy ensues from events involving earliest changes in the glomeruli and podocytes, followed by accumulation of extracellular matrix in the mesangium. Postulated mechanisms include roles for vascular endothelial growth factor (VEGF), produced by podocytes and contributing to enhanced excretion of urinary albumin and recruitment/activation of inflammatory cells, and transforming growth factor-beta (TGF-beta), elicited largely from mesangial cells and driving production of extracellular matrix. RAGE, a receptor for advanced glycation endproducts (AGEs) and S100/calgranulins, displays enhanced expression in podocytes of genetically diabetic db/db mice by age 13 weeks. RAGE-bearing podocytes express high levels of VEGF by this time, in parallel with enhanced recruitment of mononuclear phagocytes to the glomeruli; events prevented by blockade of RAGE. By age 27 weeks, soluble RAGE-treated db/db mice displayed diminished albuminuria and glomerulosclerosis, and improved renal function. Diabetic homozygous RAGE null mice failed to develop significantly increased mesangial matrix expansion or thickening of the glomerular basement membrane. We propose that activation of RAGE contributes to expression of VEGF and enhanced attraction/activation of inflammatory cells in the diabetic glomerulus, thereby setting the stage for mesangial activation and TGF-beta production; processes which converge to cause albuminuria and glomerulosclerosis.

Albuminuria↗
PubMed2002

Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes.

Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules with a diverse repertoire of ligands. These ligands include products of nonenzymatic glycation, the Advanced Glycation Endproducts (AGEs, enriched in the diabetic milieu), members of the S100/calgranulin family of proinflammatory mediators, beta-sheet fibrillar structures (characteristic of amyloid) and amphoterin (present at high levels in the tumor bed). Ligation of RAGE by its ligands upregulates expression of the receptor and triggers an ascending spiral of cellular perturbation due to sustained RAGE-mediated cellular activation. For example, in the setting of diabetes, a vascular environment rich in AGEs and S100/calgranulins accelerates atherogenesis in murine models, and this can be blocked by intercepting the interaction of ligands with RAGE. While RAGE is certainly not the cause of diabetes, it functions as a progression factor driving cellular dysfunction underlying the development of diabetic complications as the microenvironment becomes enriched in its ligands. Though further studies will be required to determine the importance of RAGE-mediated cellular activation to human chronic diseases, it represents a novel receptor-ligand system potentially impacting on a range of pathophysiologic conditions.

Animals↗
PubMed2000

Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases.

The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily of cell surface molecules, interacts with distinct molecules implicated in homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer's disease. Engagement of RAGE by a ligand triggers activation of key cell signalling pathways, such as p21ras, MAP kinases, NF-kappaB and cdc42/rac, thereby reprogramming cellular properties. RAGE is a central cell surface receptor for amphoterin, a polypeptide linked to outgrowth of cultured cortical neurons derived from developing brain. Indeed, the co-localization of RAGE and amphoterin at the leading edge of advancing neurites indicated their potential contribution to cellular migration, and in pathologies such as tumour invasion. Here we demonstrate that blockade of RAGE-amphoterin decreased growth and metastases of both implanted tumours and tumours developing spontaneously in susceptible mice. Inhibition of the RAGE-amphoterin interaction suppressed activation of p44/p42, p38 and SAP/JNK MAP kinases; molecular effector mechanisms importantly linked to tumour proliferation, invasion and expression of matrix metalloproteinases.

Animals↗
PubMed2026

Advanced glycation end products drive blood-brain barrier lipid dysregulation via RAGE-ABCA1 signaling to promote neurovascular dysfunction in Alzheimer's disease.

Neurovascular dysfunction is an early and critical contributor to Alzheimer's disease (AD), yet the molecular mechanisms linking vascular pathology to metabolic dysregulation remain incompletely understood. Advanced glycation end products (AGEs), which accumulate during aging and metabolic stress, have been implicated in AD pathology; however, their role in cerebrovascular lipid homeostasis is unclear. Here, we demonstrate that AGE accumulation within cerebral microvessels promotes lipid droplet (LD) formation in endothelial cells through receptor for AGE (RAGE)-dependent disruption of cholesterol efflux pathways. In aged APP transgenic mice and human AD brains, we observe increased AGE deposition concomitant with elevated RAGE, DGAT1, and perilipin expression, alongside reduced ABCA1 levels. In human brain endothelial cells, AGE exposure induces lipid metabolic reprogramming characterized by enhanced LD accumulation, upregulation of lipogenic machinery, and suppression of cholesterol efflux. Mechanistically, RAGE silencing restores ABCA1 expression and attenuates LD formation, identifying RAGE as a key upstream regulator. Pharmacological activation of ABCA1 reverses AGE-induced lipid accumulation and reduces RAGE expression, highlighting a therapeutic axis. Furthermore, AGE exposure disrupts blood-brain barrier (BBB) integrity and impairs amyloid-&#x3b2; transport in an in vitro BBB model. In vivo, aging is associated with progressive microvascular LD accumulation, linking metabolic dysfunction to vascular pathology. Together, our findings establish an AGE-RAGE-ABCA1 signaling axis that drives endothelial lipid dysregulation and BBB impairment, providing a mechanistic framework connecting metabolic stress to neurovascular dysfunction in AD.

Journal Article↗