S100B protects LAN‐5 neuroblastoma cells against Aβ amyloid‐induced neurotoxicity via RAGE engagement at low doses but increases Aβ amyloid neurotoxicity at high doses

Businaro, Rita; Leone, Stefano; Fabrizi, Cinzia; Sorci, Guglielmo; Donato, Rosario; Lauro, Giuliana M.; Fumagalli, Laura

doi:10.1002/jnr.20785

Cited by 85 publications

(84 citation statements)

References 47 publications

(74 reference statements)

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“…Our in vitro experiments involving oxygen-glucose deprivation showed a dual effect of exogenous S100B on neuronal survival, being neuroprotective at low doses and neurotoxic at high doses. These results are in accordance with previous studies showing survival effects of S100B at relatively low concentrations against serum deprivation, glutamate, N-methyl-D-asparatate or amyloid-␤ peptide neurotoxicity (9,11,12). The requirement of RAGE for S100B protective effects was demonstrated in some of these paradigms (9,11).…”

Section: Discussionsupporting

confidence: 92%

“…In vitro studies using primary neurons or neuroblastoma cells showed that stimulation of RAGE by low levels of S100B leads to neurite outgrowth, and activation of pro-survival pathways during stress conditions like trophic factor deprivation, glutamate, N-methyl-D-aspartate, or amyloid-␤ toxicity (9 -12). On the other hand, treatment of primary neurons, astrocytes, or microglia with relatively high doses of S100B leads to oxidative stress, NF-B activation, expression of proinflammatory mediators, and cytotoxicity (9,11,13,14). Little is…”

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confidence: 99%

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Hypoxia-inducible Factor-1 Mediates Neuronal Expression of the Receptor for Advanced Glycation End Products following Hypoxia/Ischemia

Pichiule

Chávez

Schmidt

et al. 2007

Journal of Biological Chemistry

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Activation of the receptor for advanced glycation endproducts (RAGE) by its multiple ligands can trigger diverse signaling pathways with injurious or pro-survival consequences. In this study, we show that Rage mRNA and protein levels were stimulated in the mouse brain after experimental stroke and systemic hypoxia. In both cases, RAGE expression was primarily associated with neurons. Activation of RAGE-dependent pathway(s) post-ischemia appears to have a neuroprotective role because mice genetically deficient for RAGE exhibited increased infarct size 24 h after injury. Up-regulation of RAGE expression was also observed in primary neurons subjected to hypoxia or oxygen-glucose deprivation, an in vitro model of ischemia. Treatment of neurons with low concentrations of S100B decreased neuronal death after oxygen-glucose deprivation, and this effect was abolished by a neutralizing antibody against RAGE. Conversely, high concentrations of exogenous S100B had a cytotoxic effect that seems to be RAGE-independent. As an important novel finding, we demonstrate that hypoxic stimulation of RAGE expression is mediated by the transcription factor hypoxia-inducible factor-1. This conclusion is supported by the finding that HIF-1␣ down-regulation by Cre-mediated excision drastically decreased RAGE induction by hypoxia or desferrioxamine. In addition, we showed that the mouse RAGE promoter region contains at least one functional HIF-1 binding site, located upstream of the proposed transcription start site. A luciferase reporter construct containing this RAGE promoter fragment was activated by hypoxia, and mutation at the potential HIF-1 binding site decreased hypoxia-dependent promoter activation. Specific binding of HIF-1 to this putative HRE in hypoxic cells was detected by chromatin immunoprecipitation assay.The receptor for advanced glycation end products (RAGE) 4 is a member of the immunoglobin superfamily of cell surface molecules. It was originally identified by its capacity to bind advanced glycation end products, adducts that accumulate during natural aging and are produced at an augmented rate during diabetes (1). Subsequently, several other ligands for this receptor have been reported including amyloid-␤ peptide, high-mobility group box 1, some members of the S100/calgranulin family, and Mac-1 (2-5). Multiple studies indicate that RAGE signaling has profound stimulatory effects on gene expression of inflammatory mediators, a mechanism that has been implicated in the pathogenesis of diabetic complications in the periphery (for review, see Ref. 6). In the central nervous system, the expression of RAGE has been described in several cell types. During the embryonic and early postnatal period, RAGE is highly expressed by hippocampal, cortical, and cerebellar neurons (4). Expression of this receptor is limited in the normal adult brain, but enhanced in pathological conditions like Alzheimer disease (5, 7). In this pathology, RAGE expression was observed not only in neurons but also in endothelial cells, and microglia (5, 8...

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Hypoxia-inducible Factor-1 Mediates Neuronal Expression of the Receptor for Advanced Glycation End Products following Hypoxia/Ischemia

Pichiule

Chávez

Schmidt

et al. 2007

Journal of Biological Chemistry

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“…Although S100B levels increase with normal aging [42,43], hippocampal and temporal lobe levels of S100B are significantly elevated in AD cases [26,44,45]. At micromolar extracellular concentrations, S100B can act as a cytokine, causing apoptosis and the production of reactive oxygen species (reviewed in [46,47]). Like A␤, S100B is a ligand for the receptor for advanced glycation end products (RAGE) which when activated can lead to increases in several AD-related signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease

Ferguson

Panos

Sloper

et al. 2017

JAD

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Abstract.Background: Alzheimer's disease (AD) presents with an earlier onset age and increased symptom severity in African Americans and Hispanics. Objective: Although the prevalence of plaques and tangles may not exhibit ethnicity-related differences, levels of neurodegenerative proteins have not been described. Methods: Here, levels of five proteins (i.e., S100B, sRAGE, GDNF, A␤ 40 , and A␤ 42 ) and the A␤ 42 /A␤ 40 ratio were measured in postmortem samples of the middle temporal gyrus (BA21) from age-matched African Americans and Caucasians with AD (n = 6/gender/ethnicity). Results: S100B levels were increased 17% in African Americans (p < 0.003) while sRAGE was mildly decreased (p < 0.09). A␤ 42 levels were increased 121% in African Americans (p < 0.02), leading to a 493% increase in the A␤ 42 /A␤ 40 ratio (p < 0.002). Analysis of GDNF levels did not indicate any significant effects. There were no significant effects of gender and no significant ethnicity with gender interactions on any analyte. Effect size calculations indicated "medium" to "very large" effects. Conclusion: S100B is typically elevated in AD cases; however, the increased levels in African Americans here may be indicative of increased severity in specific populations. Increased A␤ 42 /A␤ 40 ratios in the current study are compatible with increased disease severity and might indicate increased AD pathogenesis in African Americans. Overall, these results are compatible with a hypothesis of increased neuroinflammation in African Americans with AD.

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“…Important role in pathogenesis of AD and chronic complications of DM play carbohydrate-derived advanced glycation end-products (AGEs) [43]. Post-mortem analyzed samples of AD with diabetes compared to AD without diabetes or non-demented controls have shown their significant increase [44]. RAGE is specific cell surface receptor for amyloid β and it results with easier neuronal damage [45,46].…”

Section: Role Of Insulin In Overall Degradational Process In Pathogenmentioning

confidence: 99%

Does the Choice of Treatment of Diabetes Mellitus Change Natural Course of Alzheimer Disease?

Karahmet¹,

Prnjavorac²,

Sejranić³

et al. 2018

J Alzheimers Dis Parkinsonism

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IntroductionAlzheimer's disease characterized clinically by a progressive and gradual decline in cognitive function and neuropathologically, by the presence of neuronal threats, specific neuron loss, synapse loss and disturbance of cholinergic synapses. Most people with Alzheimer's have the late-onset form of the disease, in which the symptoms become apparent in their mid-60s. Genetic Basis of Metabolic Changes in Alzheimer's DiseasesThe apolipoprotein E (APOE) gene is involved in late-onset Alzheimer's. This gene has several forms. One of them, APOE ε4, increases a person's risk of developing AD and is associated with an earlier age onset. Around 0.1% of the cases are familial forms of autosomal dominant inheritance, which has an onset before age 65 [1]. This form of the disease is known as onset familial Alzheimer's disease. Most of the autosomal dominant familial AD can be attributed to mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins1 and 2 [2]. Most of the mutations in the APP and presenilin genes increase the production of a small protein called Aβ42, which is the main component of senile plaques [3]. Some of the mutations merely alter the ratio between Aβ42 and the other major forms particularly Aβ40 without increasing Aβ42 levels [4,5]. The major hallmarks of AD pathology are masses of the extracellular β-amyloid peptide (Aβ) and neurofibrillary tangles of the microtubule binding protein tau [6,7]. Aβ has crucial importance in the relation of AD as well as the crucial role of its pathogenesis. The neurotoxic potential of the Aβ peptide results from its biochemical properties, favoring aggregation into insoluble oligomers and protofibrils [7]. Etiological treatment of AD is AbstractAlzheimer disease (AD) is common worldwide and almost every case has comorbidities. One of the most common comorbidities of AD is Diabetes mellitus (DM), with or without metabolic syndrome. Both diseases effect nerve tissue and successful treatment would improve the status of the patient. In patients with Alzheimer disease treatment of DM, the treatment could be harmful to the AD, because of that high insulin intake. This may lead to progression of AD. Insulin is considered the best treatment for DM, but insulin therapy could increase comorbidity with AD. No specific therapy for AD is known up to date, so because of that DM is one of the most important risk for AD, concomitant therapy for DM should be planned very carefully. All options of DM therapy should be considered, and different mechanisms of anti-diabetic drugs are preferable. Treatment of AD is more complex metabolic syndrome is present. Any inflammation causes local tissue damage, including brain tissue during AD. Release of interleukins, primarily TNF-α, IL-6, IL-1β in the presence of adipokine leptin, maintains chronic inflammatory status in local brain tissue. Thus, low doses of immunosuppressant therapy should be considered for treatment of AD in future. To delay apoptosis of nerve tissue cells, brain and nerve tissue...

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S100B protects LAN‐5 neuroblastoma cells against Aβ amyloid‐induced neurotoxicity via RAGE engagement at low doses but increases Aβ amyloid neurotoxicity at high doses

Cited by 85 publications

References 47 publications

Hypoxia-inducible Factor-1 Mediates Neuronal Expression of the Receptor for Advanced Glycation End Products following Hypoxia/Ischemia

Hypoxia-inducible Factor-1 Mediates Neuronal Expression of the Receptor for Advanced Glycation End Products following Hypoxia/Ischemia

Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease

Does the Choice of Treatment of Diabetes Mellitus Change Natural Course of Alzheimer Disease?

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