Kavalactones Protect Neural Cells against Amyloid β Peptide-Induced Neurotoxicity via Extracellular Signal-Regulated Kinase 1/2-Dependent Nuclear Factor Erythroid 2-Related Factor 2 Activation

Wruck, Christoph Jan; Götz, Mario E.; Herdegen, Thomas; Varoga, Deike; Brandenburg, Lars‐Ove; Pufe, Thomas

doi:10.1124/mol.107.042499

Cited by 107 publications

(80 citation statements)

References 38 publications

(38 reference statements)

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“…Thus, SKN-1 appears functionally analogous to Nrf2, the best-studied member of the Nrf family, which controls phase II detoxification response genes and is centrally involved in cellular responses to oxidative stress (reviewed in Osburn and Kensler 2008). Nrf2 activation, either by tert-butylhydroquinone treatment or viral Nrf2 gene transfection, has been shown to be protective in an APP/PS1 transgenic mouse model (Kanninen et al 2008(Kanninen et al , 2009, as well as in neuronal cells exposed to exogenous Ab (Wruck et al 2008). Interestingly, a polymorphism in the human Nrf2 gene, NFE2L2, has recently been associated with earlier AD onset (Von Otter et al 2010).…”

Section: Resultsmentioning

confidence: 99%

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

2010

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Epidemiological studies have reported that coffee and/or caffeine consumption may reduce Alzheimer's disease (AD) risk. We found that coffee extracts can similarly protect against b-amyloid peptide (Ab) toxicity in a transgenic Caenorhabditis elegans Alzheimer's disease model. The primary protective component(s) in this model is not caffeine, although caffeine by itself can show moderate protection. Coffee exposure did not decrease Ab transgene expression and did not need to be present during Ab induction to convey protection, suggesting that coffee exposure protection might act by activating a protective pathway. By screening the effects of coffee on a series of transgenic C. elegans stress reporter strains, we identified activation of the skn-1 (Nrf2 in mammals) transcription factor as a potential mechanism of coffee extract protection. Inactivation of skn-1 genetically or by RNAi strongly blocked the protective effects of coffee extract, indicating that activation of the skn-1 pathway was the primary mechanism of coffee protection. Coffee also protected against toxicity resulting from an aggregating form of green fluorescent protein (GFP) in a skn-1-dependent manner. These results suggest that the reported protective effects of coffee in multiple neurodegenerative diseases may result from a general activation of the Nrf2 phase II detoxification pathway.

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Section: Resultsmentioning

confidence: 99%

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

2010

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“…Stimulation of a human hepatic cell line with the well estabished Nrf2 activators methysticin (18) and sulforaphane (21) leads to a significant enhanced IL-6 secretion (Fig. 3).…”

Section: Discussionmentioning

confidence: 99%

“…18. pIL6-luc651 or pIL6-luc651⌬ARE reporter plasmids and pRL-TK plasmids (Promega) were cotransfected into HepG2-cells.…”

Section: Methodsmentioning

confidence: 99%

Nrf2 Induces Interleukin-6 (IL-6) Expression via an Antioxidant Response Element within the IL-6 Promoter

Wruck

Streetz

Pavic

et al. 2011

Journal of Biological Chemistry

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115

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IL-6 gene expression is controlled by a promoter region containing multiple regulatory elements such as NF-B, NF-IL6, CRE, GRE, and TRE. In this study, we demonstrated that TRE, found within the IL-6 promoter, is embedded in a functional antioxidant response element (ARE) matching an entire ARE consensus sequence. Further, point mutations of the ARE consensus sequence in the IL-6 promoter construct selectively eliminate ARE but not TRE activity. Nrf2 is a redox-sensitive transcription factor which provides cytoprotection against electrophilic and oxidative stress and is the most potent activator of ARE-dependent transcription. Using Nrf2 knock-out mice we demonstrate that Nrf2 is a potent activator of IL-6 gene transcription in vivo. Moreover, we show evidence that Nrf2 is the transcription factor that activates IL6 expression in a cholestatic hepatitis mouse model. Our findings suggest a possible role of IL-6 in oxidative stress defense and also give indication about an important function for Nrf2 in the regulation of hematopoietic and inflammatory processes.Because of its diverse biological function and simultaneous description in different studies, IL-6 was initially assigned several names. It was identified as a T-cell-derived B-cell differentiation factor, as it induced activated B-cells into antibody-producing cells: interferon-␤2 (26 kDa protein), a hybridoma/plasmacytoma growth factor and a hepatocytestimulating factor. The name IL-6 was proposed when the cDNA nucleotide sequences for these proteins had been determined, and the molecules were found to be identical (1). In addition, IL-6 plays a key role in inflammation, being the main inducer of fibrinogen, serum amyloid A protein, the acute phase response and is one of the most important mediators of fever. In muscle and fatty tissues, IL-6 stimulates energy mobilization.The IL-6 promoter is rapidly activated by cytokines, including IL-1 and TNF-␣, as well as by phorbol esters and cyclic AMP. The promoter-region of the IL-6 gene contains multiple regulatory elements such as nuclear factor-B (NF-B), nuclear factor-IL6 (NF-IL6) (also referred to as C/EBP␤), cAMP response element (CRE), TPA (12-O-tetradecanoylphorbol-13-acetate) responsive element (TRE; also referred to as the AP-1 binding site), and the glucocorticoid response element (GRE) (2).Structurally related to TRE is the antioxidant responsive element (ARE, 2 also referred to as the electrophile responsive element (EpRE)) (3, 4). Some TREs are found to be embedded within an ARE, such as in the promoter region of human NAD(P)H:quinine oxidoreductase-1 (NQO1), rat and mouse glutathione S-transferase (GST) Ya subunit, and rat GST-P (5). ARE is commonly found in the promoter region of genes encoding phase II detoxification as well as antioxidant enzymes such as NQO1, thioredoxin, thioredoxin reductase, glutathione peroxidase, and hemeoxygenase-1 (6). Analyses of ARE-nuclear protein complexes have identified numerous nuclear transcription factors including c-Jun, Jun-B, Jun-D, c-Fos, Fra1, Nrf1, Nrf2, ...

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“…C. elegans SKN-1 is the functional orthologue of the mammalian protein Nrf2 (nuclear factor-E2-related factor 2), controlling the induction of multiple genes involved in detoxification and antioxidant stress response (Kahn et al, 2008). Nrf2 activation has been suggested to be protective in several neurodegenerative conditions, including neurons exposed to A␤ and a mouse model of AD (Kanninen et al, 2008(Kanninen et al, , 2009Wruck et al, 2008). It was also suggested that Nrf2 induction can be modulated by copper (Calay et al, 2010;Wang et al, 2010;Simmons et al, 2011).…”

Section: Copper Treatment Delays A␤-induced Paralysis In a Temperaturmentioning

confidence: 99%

Copper Reduces A Oligomeric Species and Ameliorates Neuromuscular Synaptic Defects in a C. elegans Model of Inclusion Body Myositis

Rebolledo¹,

Aldunate²,

Kohn³

et al. 2011

Journal of Neuroscience

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Alzheimer's disease and inclusion body myositis (IBM) are disorders frequently found in the elderly and characterized by the presence of amyloid-␤ peptide (A␤) aggregates. We used Caenorhabditis elegans that express A␤ in muscle cells as a model of IBM, with the aim of analyzing A␤-induced muscle pathology and evaluating the consequences of modulating A␤ aggregation.First, we tested whether the altered motility we observed in the A␤ transgenic strain could be the result of a compromised neuromuscular synapse. Our pharmacological analyses show that synaptic transmission is defective in our model and suggest a specific defect on nicotine-sensitive acetylcholine receptors (AChRs). Through GFP-coupled protein visualization, we found that synaptic dysfunction correlates with mislocalization of ACR-16, the AChR subunit essential for nicotine-triggered currents.Histological and biochemical analysis allowed us to determine that copper treatment increases the amyloid deposits and decreases A␤ oligomers in this model. Furthermore, copper treatment improves motility, ACR-16 localization, and synaptic function and delays A␤-induced paralysis. Our results indicate that copper modulates A␤-induced pathology and suggest that A␤ oligomers are triggering neuromuscular dysfunction. Our findings emphasize the importance of neuromuscular synaptic dysfunction and the relevance of modulating the amyloidogenic component as an alternative therapeutic approach for this debilitating disease.

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Kavalactones Protect Neural Cells against Amyloid β Peptide-Induced Neurotoxicity via Extracellular Signal-Regulated Kinase 1/2-Dependent Nuclear Factor Erythroid 2-Related Factor 2 Activation

Cited by 107 publications

References 38 publications

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

Nrf2 Induces Interleukin-6 (IL-6) Expression via an Antioxidant Response Element within the IL-6 Promoter

Copper Reduces A Oligomeric Species and Ameliorates Neuromuscular Synaptic Defects in a C. elegans Model of Inclusion Body Myositis

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