Nuclear factor erythroid 2-related factor 2 protects against beta amyloid

Kanninen, Katja M.; Malm, Tarja; Jyrkkänen, Henna‐Kaisa; Goldsteins, Gundars; Keksa-Goldsteine, Velta; Tanila, Heikki; Yamamoto, Masayuki; Ylä‐Herttuala, Seppo; Levonen, Anna–Liisa; Koistinaho, Jari

doi:10.1016/j.mcn.2008.07.010

Cited by 222 publications

(187 citation statements)

References 64 publications

Supporting

Mentioning

173

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

2010

View full text Add to dashboard Cite

show abstract

“…In these cases of increased cell dysfunction and damage and physiological morbidity, Glo1 induction was insufficient to prevent increased protein damage by MG. The mechanism of induction was unknown but can now be linked to the endogenous Nrf2-mediated antistress gene response known to be activated in these conditions [33][34][35][36]. Studies with Glo1 overexpressing transgenic animals have indicated that increased expression of Glo1 has beneficial effect -maintenance of vascular cell responses, prevention of myocardial cell death when oxygenated after ischaemia and delay of ageing and senescence [13;37;38].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation

Xue

Rabbani

Momiji

et al. 2012

Biochemical Journal

Self Cite

262

230

View full text Add to dashboard Cite

Word count: 5056. 2 SYNOPSISAbnormal cellular accumulation of the dicarbonyl metabolite methylglyoxal occurs on exposure to high glucose concentration, inflammation, cell ageing and senescence. It is associated with increased methylglyoxal-adduct content of protein and DNA linked to increased DNA strand breaks and mutagenesis, mitochondrial dysfunction and reactive oxygen species formation and cell detachment from the extracellular matrix. Methylglyoxalmediated damage is countered by glutathione-dependent metabolism by glyoxalase-1. It is not known, however, if glyoxalase-1 has stress responsive up-regulation to counter periods of high methylglyoxal concentration or dicarbonyl stress. We identified a functional antioxidant response element in the 5'-untranslated region of exon-1 of the mammalian glyoxalase-1 gene. Transcription factor Nrf2 binds to this antioxidant response element increasing basal and inducible expression of glyoxalase 1. Activators of Nrf2 induced increased glyoxalase-1 mRNA, protein and activity. Increased expression of glyoxalase-1 decreased cellular and extracellular concentrations of methylglyoxal, methylglyoxal -derived protein adducts, mutagenesis and cell detachment. Hepatic, brain, heart, kidney and lung glyoxalase-1 mRNA and protein were decreased in Nrf2 (-/-) mice and urinary excretion of methylglyoxal protein and nucleotide adducts were increased ca. 2-fold. We conclude that dicarbonyl stress is countered by up-regulation of glyoxalase-1 in the Nrf2 stress responsive system, protecting protein and DNA from increased damage and preserving cell function.Key words: Nrf2, glyoxalase, methylglyoxal, DNA damage, protein damage, glycation.Abbreviations used: AITC, allyl isothiocyanate; ARE, antioxidant response element; CDDOMe, methyl 2-cyano-3,12-dioxo-oleana-1,9(11)dien-28-oate; ChIP, chromatin immunoprecipitation; CNC, cap 'n' collar; ECL, enhanced chemiluminescence; Glo1, glyoxalase 1; keap1, kelch (β-propeller tertiary structure)-like erythroid cell-derived protein with CNC homology-associated protein 1; IRE, insulin response element; MG, methylglyoxal; MGdG, 3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purin-9(8)one; MG-H1, N  -(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine; Nrf2, nuclear erythroid factor E2 related factor-2; ROS, reactive oxygen species; SFN, sulforaphane; TBST, tris-buffered saline with Tween-20. 3 INTRODUCTIONModification of proteins and DNA by the dicarbonyl metabolite methylglyoxal (MG) has emerged as an important endogenous threat to the functional integrity of the proteome and genome. MG is formed by the spontaneous degradation of triosephosphate intermediates and is an unavoidable by-product of anaerobic glycolysis [1]. MG reacts with proteins and DNA forming quantitatively major adducts of endogenous damage, similar to and in some cases exceeding the steady-state levels of adducts produced by oxidative damage. Modification of proteins by MG is directed to arginine residues forming the hydroimidazolone, N  -(5-hydro-5-methyl-4-imi...

show abstract

“…Nuclear response factor 2 (Nrf2) and Nrf2/antioxidant response element have been proposed as a therapeutic target for autophagy and mitophagy. In transgenic AD mouse models intrahippocampal injections of the lentiviral vector expressing Nrf2 decreased Aβ plaque, reduced learning deficits, and protected against Aβ-induced cell death [158,159]. Synthetic triterpenoids have been demonstrated to induce expression of Nrf2 and to protect against cell death in both in vitro and in vivo experiments [160,161].…”

Section: Apoptosis and Mitophagy As Therapeutic Targetsmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

View full text Add to dashboard Cite

Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

show abstract

Nuclear factor erythroid 2-related factor 2 protects against beta amyloid

Cited by 222 publications

References 64 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

Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Contact Info

Product

Resources

About