Inhibition of JNK/dFOXO pathway and caspases rescues neurological impairments in Drosophila Alzheimer’s disease model

Hong, Yong Deog; Lee, Soojin; Park, Seung-Hwan; Lee, Jang Ho; Han, Sang-Jae; Kim, Sang‐Tae; Kim, Young‐Kyoon; Jeon, Songhee; Koo, Byung-Soo; Cho, Kyoung Sang

doi:10.1016/j.bbrc.2012.01.122

Cited by 59 publications

(59 citation statements)

References 32 publications

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“…16) Here, we show that expression of Aβ42 in fly neurons increased ERK activation and glial cell proliferation, which are not a consequence of Aβ42-induced apoptosis. These results suggest that Aβ42 exerts its toxicity in Drosophila neurons via various pathways, including activation of the JNK and ERK signaling pathways and inflammation as is observed in the brains of human AD patients.…”

Section: Discussionmentioning

confidence: 58%

“…[12][13][14][15] We previously showed that overexpression of Aβ42 in Drosophila neurons induced JNK activation, which leads to cell death via caspase-dependent apoptosis. 15,16) Similar to JNK, ERK has been shown to be activated in degenerating AD neurons 17,18) and APP transgenic mouse models. 19) ERK hyperactivation has also been implicated in AD pathology.…”

Section: Suppressive Effects Of Suhexiang Wan On Amyloid-β42-induced mentioning

confidence: 99%

“…Climbing Assay The climbing assay was performed as described previously 16,41) with some modifications. Ten male flies were incubated for 1 h at 25°C in climbing ability test vials for environmental acclimation.…”

Section: Preparation Of Ksop1009 Extract and Treatment With Ksop1009 mentioning

confidence: 99%

“…We previously showed that ectopic expression of Aβ42 induced apoptosis via the JNK pathway in Drosophila neurons. 16) Therefore, we tested if the elevation in ERK phosphorylation levels is the result of Aβ42-induced apoptosis by assessing pERK levels in flies co-expressing Aβ42 and Drosophila inhibitor of apoptosis protein 1 (DIAP1), which strongly suppresses Aβ42-induced apoptosis (Fig. 1C).…”

Section: Aβ42mentioning

confidence: 99%

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Suppressive Effects of SuHeXiang Wan on Amyloid-β42-Induced Extracellular Signal-Regulated Kinase Hyperactivation and Glial Cell Proliferation in a Transgenic <i>Drosophila</i> Model of Alzheimer’s Disease

Park

Lee

Hong

et al. 2013

Biological & Pharmaceutical Bulletin

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SuHeXiang Wan (SHXW), a Chinese traditional medicine, has been used to treat infantile convulsions, seizures and strokes. Previously, we reported that modified SHXW, called KSOP1009, suppressed the hyperactivation of c-Jun N-terminal kinase (JNK) and Alzheimer's disease (AD)-like phenotypes in amyloid-β42 (Aβ42)-expressing Drosophila AD models. In the present study, we, further, investigated the detailed mechanism by which KSOP1009 suppresses the AD-like phenotypes of the model flies. As seen in the brains of AD patients, pan-neuronal expression of Aβ42 in Drosophila increased activation of extracellular signal-regulated kinase (ERK), which was monitored by its phosphorylation level, and the number of glial cells in the brain. Suppression of caspase activity did not affect these phenomena, suggesting that Aβ42 induces ERK activation and glial cell proliferation independently of apoptotic processes. KSOP1009 intake significantly reduced the level of ERK activation and the number of glial cells. Moreover, KSOP1009 intake also effectively decreased the defects in the wing vein formation induced by Epidermal growth factor receptor (Egfr) overexpression in fly wings, suggesting that it may contain an inhibitory substance that inhibits the EGFR/ERK signaling pathway. In addition, the Aβ42-induced locomotive defect was partially rescued by inhibition of the elevated ERK activity through its antagonistic drug treatment. Taken together, these results suggest that KSOP1009 exerts its therapeutic effect by inhibiting the EGFR/ERK pathway and glial cell proliferation and by suppressing the JNK pathway and apoptosis.

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Section: Discussionmentioning

confidence: 58%

Section: Suppressive Effects Of Suhexiang Wan On Amyloid-β42-induced mentioning

confidence: 99%

Section: Preparation Of Ksop1009 Extract and Treatment With Ksop1009 mentioning

confidence: 99%

Section: Aβ42mentioning

confidence: 99%

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Suppressive Effects of SuHeXiang Wan on Amyloid-β42-Induced Extracellular Signal-Regulated Kinase Hyperactivation and Glial Cell Proliferation in a Transgenic <i>Drosophila</i> Model of Alzheimer’s Disease

Park

Lee

Hong

et al. 2013

Biological & Pharmaceutical Bulletin

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“…Furthermore, increased FoxO activity can function in concert with tribbles pseudokinase 3 to result in apoptotic and autophagic Aβ induced neuronal cell death (79). Inhibition of FoxO activity under such conditions can protect against oxidative stress and Aβ toxicity (208, 229). …”

Section: Foxo Transcription Factorsmentioning

confidence: 99%

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

Maiese¹

2018

CNR

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BACKGROUND With the global increase in life span expectancy, neurodegenerative disorders continue to affect an ever increasing number of individuals throughout the world. New treatment strategies for neurodegenerative diseases are desperately required given the lack of current treatment modalities. METHODS Here we examine novel strategies for neurodegenerative disorders that include circadian clock genes, non-coding ribonucleic acids (RNAs), and the mammalian forkhead transcription factors of the O class (FoxOs). RESULTS Circadian clock genes, non-coding RNAs, and FoxOs offer exciting prospects to potentially limit or remove the significant disability and death associated with neurodegenerative disorders. Each of these pathways have an intimate relationship with the programmed death pathways of autophagy and apoptosis and share a common link to the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and the mechanistic target of rapamycin (mTOR). Circadian clock genes are necessary to modulate autophagy, limit cognitive loss, and prevent neuronal injury. Non-coding RNAs can control neuronal stem cell development and neuronal differentiation and offer protection against vascular disease such as atherosclerosis. FoxOs provide exciting prospects to block neuronal apoptotic death and to activate pathways of autophagy to remove toxic accumulations in neurons that can lead to neurodegenerative disorders. CONCLUSIONS Continued work with circadian clock genes, non-coding RNAs, and FoxOs can offer new prospects and hope for the development of vital strategies for the treatment of neurodegenerative diseases. These innovative investigative avenues have the potential to significantly limit disability and death from these devastating disorders.

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Inhibition of c‐Jun N‐terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice

Zhou

Wang

et al. 2015

Annals of Neurology

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Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathological features and ameliorating cognitive deficits associated with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides critical preclinical evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD.

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Inhibition of JNK/dFOXO pathway and caspases rescues neurological impairments in Drosophila Alzheimer’s disease model

Cited by 59 publications

References 32 publications

Suppressive Effects of SuHeXiang Wan on Amyloid-β42-Induced Extracellular Signal-Regulated Kinase Hyperactivation and Glial Cell Proliferation in a Transgenic <i>Drosophila</i> Model of Alzheimer’s Disease

Suppressive Effects of SuHeXiang Wan on Amyloid-β42-Induced Extracellular Signal-Regulated Kinase Hyperactivation and Glial Cell Proliferation in a Transgenic <i>Drosophila</i> Model of Alzheimer’s Disease

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

Inhibition of c‐Jun N‐terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice

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