JNK3 Perpetuates Metabolic Stress Induced by Aβ Peptides

Yoon, Sung Ok; Park, Dong Ju; Ryu, Jae Cheon; Özer, Hatice Gülçin; Tep, Chhavy; Shin, Yong Jae; Lim, Tae Hee; Pastorino, Lucia; Kunwar, Ajaya Jang; Walton, James C.; Nagahara, Alan H.; Lu, Kun Ping; Nelson, Randy J.; Tuszynski, Mark H.; Huang, Kun

doi:10.1016/j.neuron.2012.06.024

Cited by 210 publications

(186 citation statements)

References 76 publications

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“…20 Enhanced JNK3 levels could be linked to Ab-induced endoplasmic reticulum (ER) stress, which has been reported to be increased in Alzheimer disease brains. 14,34 In addition, ER stress is implicated in JNK3 regulation in cellular models. 14 A previous systematic search for global gene expression in Alzheimer disease also showed an increase of JNK cascade cluster in patients in late Braak stages.…”

Section: Discussionmentioning

confidence: 99%

“…12 Previous studies implicating JNKs in the pathogenesis of Alzheimer disease have shown that JNKs, particularly JNK3, can phosphorylate APP, enhancing Ab production. 13,14 JNK activity can also raise BACE1 expression 15 and is detected in granulovacuolar degeneration. 16 Activated JNKs are increased in Alzheimer disease brains 17 as well as some upstream JNK activators, such as JKK1.…”

Section: J Psychiatry Neurosci 2015;40(3)mentioning

confidence: 99%

“…20,21 Ab-induced cell death is reduced in cultures of cortical neurons from JNK3 knockout (KO) mice, 22 and JNKs have been implicated in experimental models of Alzheimer and Parkinson diseases. 14,23,24 JNK3 may be detrimental to neurons, but no study has evaluated the levels of JNK3 in Alzheimer disease brains and in the CSF of living patients with Alzheimer disease. To our knowledge, our study is the first to show that JNK3 levels are increased in the CSF of patients with Alzheimer disease and that they are linked to cognitive decline in affected patients.…”

Section: J Psychiatry Neurosci 2015;40(3)mentioning

confidence: 99%

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Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

Gourmaud

Paquet

Dumurgier

et al. 2015

jpn

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Section: Discussionmentioning

confidence: 99%

Section: J Psychiatry Neurosci 2015;40(3)mentioning

confidence: 99%

Section: J Psychiatry Neurosci 2015;40(3)mentioning

confidence: 99%

See 1 more Smart Citation

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

Gourmaud

Paquet

Dumurgier

et al. 2015

jpn

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“…JNK activation has been observed in various neurodegenerative disorders where the JNK signaling cascade has been shown to cause neuronal cell death (15)(16)(17)(18)(19). Importantly, postmortem studies, along with MPTP and 6-OHDA animal models of neurodegeneration, showed an important role for JNK in the disease pathogenesis (15,16,19).…”

mentioning

confidence: 99%

Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway

Iqbal

Howard

LoGrasso

2015

Molecular and Cellular Biology

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Serum glucocorticoid kinase 1 (SGK1) has been shown to be protective in models of Parkinson's disease, but the details by which it confers benefit is unknown. The current study was designed to investigate the details by which SGK1 confers neuroprotection. To do this we employed a cellular neurodegeneration model to investigate c-Jun N-terminal kinase (JNK) signaling and endoplasmic reticulum (ER) stress induced by 6-hydroxydopamine. SGK1-expressing adenovirus was created and used to overexpress SGK1 in SH-SY5Y cells, and dexamethasone was used to increase endogenous expression of SGK1. Oxidative stress, mitochondrial dysfunction, and cell death were monitored to test the protective effect of SGK1. To investigate the effect of SGK1 overexpression in vivo, SGK1-expressing adenovirus was injected into the striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and protection of dopaminergic neurons was quantitatively assessed by tyrosine hydroxylase immunohistochemistry. SGK1 overexpression was found to decrease reactive oxygen species generation, alleviate mitochondrial dysfunction, and rescue cell death in vitro and in vivo by inactivating mitogen-activated protein kinase kinase 4 (MKK4), JNK, and glycogen synthase kinase 3␤ (GSK3␤) and thereby decreasing ER and oxidative stress. These results suggest that therapeutic strategies for activation of SGK1 may have the potential to be neuroprotective by deactivating the JNK and GSK3␤ pathways.S erum-and glucocorticoid-inducible kinase 1 (SGK1) belongs to the AGC family of kinases and has been shown to have various cellular functions, including the promotion of cell survival (1-3). SGK1 is activated by insulin and growth factors via phosphoinositide 3-kinase (PI3K), 3-phosphoinositide-dependent kinase 1 (PDK1), and mammalian target of rapamycin complex 2 (mTORC2) (4, 5). SGK1 shares its functions and some substrates with another kinase from the AGC family, protein kinase B (PKB/ Akt). Akt, like SGK1, has been shown to mediate cell survival through various signaling cascades and gets activated by a wide range of extracellular stimuli (6). SGK1 lacks the pleckstrin homology (PH) domain that tethers Akt to the plasma membrane, making SGK1 more accessible to cytosolic and nuclear sites and thereby providing it with cellular functions and substrates that do not overlap those of Akt (1, 6). SGK1 plays a protective role in oxidative stress conditions as small interfering RNA (siRNA) knockdown of SGK1 has shown an increase in oxidative stressinduced cell death in HEK293 cells (7). Oxidative stress is a hallmark of neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) (8). In a study published in 2005 by Schoenebeck et al., upregulation of SGK1 was seen in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model and in a transgenic model of ALS (SOD1-G93A), and protection from cell death was observed for animals treated with dexamethasone (De...

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“…6 It has been suggested that the toxicity of Aβ is associated with the c-Jun N-terminal kinase (JNK) pathway. 7,8 Cell apoptosis needs extracellular signals to be transmitted to the nucleus, for which the JNK pathway is suggested to be critical. 9 The JNK signaling pathway is one of the important pathways of the mitogen-activated protein kinase (MAPK) family.…”

Section: Introductionmentioning

confidence: 99%

Curcumin reduces hippocampal neuron apoptosis and JNK-3 phosphorylation in rats with Aβ-induced Alzheimer's disease: protecting spatial learning and memory

Wang¹,

Li²,

Wang³

et al. 2017

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Amyloid-β peptide (Aβ) toxicity in Alzheimer's disease (AD) is associated with the c-Jun N-terminal kinase (JNK) signaling pathway. Curcumin may prevent Aβ fiber formation, slowing AD progression. A model of AD was established in 32 Sprague Dawley rats by injection of 10 μg Aβ 1-40 into the right hippocampus. Saline was used in sham control (n=16). Sixteen AD model rats received 300 mg/kg curcumin and another 16 received saline daily for 7 days. Spatial learning and memory were assessed using a Morris water maze. Hippocampus neuron apoptosis and hippocampal levels of JNK-3 and p-JNK-3 were assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling, reverse transcription-polymerase chain reaction and Western blotting. Aβ 1-40 injection induced slower spatial learning, memory deficit, neuronal apoptosis and increased JNK-3 expression and phosphorylation (all P<0.05). Curcumin relieved spatial learning and memory deficits, hippocampus neuronal apoptosis, and reduced JNK-3 and p-JNK-3 levels (all P<0.05). In conclusion, curcumin may inhibit JNK-3 phosphorylation to protect against hippocampal neuron apoptosis after Aβ injection.

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JNK3 Perpetuates Metabolic Stress Induced by Aβ Peptides

Cited by 210 publications

References 76 publications

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway

Curcumin reduces hippocampal neuron apoptosis and JNK-3 phosphorylation in rats with Aβ-induced Alzheimer's disease: protecting spatial learning and memory

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JNK3 Perpetuates Metabolic Stress Induced by Aβ Peptides

Cited by 210 publications

References 76 publications

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway

Curcumin reduces hippocampal neuron apoptosis and JNK-3 phosphorylation in rats with A&beta;-induced Alzheimer&#39;s disease: protecting spatial learning and memory

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Curcumin reduces hippocampal neuron apoptosis and JNK-3 phosphorylation in rats with Aβ-induced Alzheimer's disease: protecting spatial learning and memory