RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis

Ray, Rashmi; Juranek, Judyta K.; Rai, Vivek

doi:10.1016/j.neubiorev.2015.12.006

Cited by 117 publications

(115 citation statements)

References 103 publications

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“…RAGE is a multi-ligand receptor that binds HMGB1, Aβ, and advanced glycation end products [56]. It is possible that RAGE may also bind tau oligomers and initiate pro-inflammatory signaling through the RAS, p38, and nuclear factor- κ B (NF κ B) pathway [56]. The NF κ B transcription factor increases the expression of HMGB1 and its receptor RAGE, increasing pro-inflammatory RAGE signaling by a feed-forward mechanism [57, 58].…”

Section: Discussionmentioning

confidence: 99%

Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases

Nilson

English

Gerson

et al. 2016

JAD

141

127

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It is well-established that inflammation plays an important role in Alzheimer’s disease (AD) and frontotemporal lobar dementia (FTLD). Inflammation and synapse loss occur in disease prior to the formation of larger aggregates, but the contribution of tau to inflammation has not yet been thoroughly investigated. Tau pathologically aggregates to form large fibrillar structures known as tangles. However, evidence suggests that smaller soluble aggregates, called oligomers, are the most toxic species and form prior to tangles. Furthermore, tau oligomers can spread to neighboring cells and between anatomically connected brain regions. In addition, recent evidence suggests that inspecting the retina may be a window to brain pathology. We hypothesized that there is a relationship between tau oligomers and inflammation, which are hallmarks of early disease. We conducted immunofluorescence and biochemical analyses on tauopathy mice, FTLD, and AD subjects. We showed that oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine. Additionally, we show that tau oligomers are present in the retina and are associated with inflammatory cells suggesting that the retina may be a valid non-invasive biomarker for brain pathology. These results suggest that there may be a toxic relationship between tau oligomers and inflammation. Therefore, the ability of tau oligomers to spread may initiate a feed-forward cycle in which tau oligomers induce inflammation, leading to neuronal damage, and thus more inflammation. Further mechanistic studies are warranted in order to understand this relationship, which may have critical implications for improving the treatment of tauopathies.

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Section: Discussionmentioning

confidence: 99%

Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases

Nilson

English

Gerson

et al. 2016

JAD

141

127

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show abstract

“…Previous studies proved that IL-6 is upregulated in thymic epithelial cells in MG patients25 and impaired expression of IL-6 among other cytokines is believed to play a role in the inflammatory response in MG26. EN-RAGE is a ligand for the receptor for advanced glycation end products (RAGE), a well-known pro-inflammatory receptor that is involved in diabetic neuropathy, cardiovascular disorders and neuroinflammatory and neurodegenerative disorders2728. Binding of EN-RAGE to RAGE activates the transcription factor NF-κB, induces secretion of cytokines and has pro-inflammatory effects on lymphocytes, neutrophils and endothelial cells29.…”

Section: Discussionmentioning

confidence: 99%

Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients

Molin

Westerberg

Punga

2017

Sci Rep

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This study describes specific patterns of elevated inflammatory proteins in clinical subtypes of myasthenia gravis (MG) patients. MG is a chronic, autoimmune neuromuscular disease with antibodies most commonly targeting the acetylcholine receptors (AChRab), which causes fluctuating skeletal muscle fatigue. MG pathophysiology includes a strong component of inflammation, and a large proportion of patients with early onset MG additionally present thymus hyperplasia. Due to the fluctuating nature and heterogeneity of the disease, there is a great need for objective biomarkers as well as novel potential inflammatory targets. We examined the sera of 45 MG patients (40 AChRab seropositive and 5 AChRab seronegative), investigating 92 proteins associated with inflammation. Eleven of the analysed proteins were significantly elevated compared to healthy controls, out of which the three most significant were: matrix metalloproteinase 10 (MMP-10; p = 0.0004), transforming growth factor alpha (TGF-α; p = 0.0017) and extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE) (also known as protein S100-A12; p = 0.0054). Further, levels of MMP-10, C-X-C motif ligand 1 (CXCL1) and brain derived neurotrophic factor (BDNF) differed between early and late onset MG. These novel targets provide valuable additional insight into the systemic inflammatory response in MG.

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“…Huntington's disease, as well as in CLN1 and diabetic neuropathy (Martini & Willison, 2016;Ray et al, 2016;Saha et al, 2008). Whether this pathway is a promising target for treatment approaches in some of these CNS disorders should be investigated in the future.…”

Section: Amyotophic Lateral Sclerosismentioning

confidence: 99%

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

Groh

Martini

2017

Glia

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Genetically caused neurological disorders of the central nervous system (CNS) are usually orphan diseases with poor or even fatal clinical outcome and few or no treatments that will improve longevity or at least quality of life. Neuroinflammation is common to many of these disorders, despite the fact that a plethora of distinct mutations and molecular changes underlie the disorders. In this article, data from corresponding animal models are analyzed to define the roles of innate and adaptive inflammation as modifiers and amplifiers of disease. We describe both common and distinct patterns of neuroinflammation in genetically mediated CNS disorders and discuss the contrasting mechanisms that lead to adverse versus neuroprotective effects. Moreover, we identify the juxtaparanode as a neuroanatomical compartment commonly associated with inflammatory cells and ongoing axonopathic changes, in models of diverse diseases. The identification of key immunological effector pathways that amplify neuropathic features should lead to realistic possibilities for translatable therapeutic interventions using existing immunomodulators. Moreover, evidence emerges that neuroinflammation is not only able to modify primary neural damage-related symptoms but also may lead to unexpected clinical outcomes such as neuropsychiatric syndromes.

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RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis

Cited by 117 publications

References 103 publications

Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases

Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases

Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

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