Neuron Specific Toxicity of Oligomeric Amyloid-β: Role for JUN-Kinase and Oxidative Stress

Ebenezer, Philip J.; Weidner, Adam M.; LeVine, Harry; Markesbery, William R.; Murphy, Michael P.; Zhang, Le; Dasuri, Kalavathi; Fernandez-Kim, Sun Ok; Bruce‐Keller, Annadora J.; Gavilán, Elena; Keller, Jeffrey N.

doi:10.3233/jad-2010-101161

Cited by 50 publications

(38 citation statements)

References 33 publications

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“…29 Studies suggest that Ab exerts neuronal toxicity through the generation of excessive ROS following mitochondria superoxide accumulation. 30 Oxidative stress can cause cellular damage because the ROS oxidizes vital cellular components, including lipids and nucleic acids, and consequently contributes to the pathophysiology of neurodegenerative diseases such as AD. 31 The ROS can destroy the integrity of the neuronal cell membrane because of lipid oxidation, resulting in the release of bioactive substances into the extracellular space, such as LDH.…”

Section: Discussionmentioning

confidence: 99%

The Role of 6-Gingerol on Inhibiting Amyloid β Protein-Induced Apoptosis in PC12 Cells

Zeng

Zong

Zhang

et al. 2015

Rejuvenation Research

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Our previous study suggests that ginger root extract can reverse behavioral dysfunction and prevent Alzheimer's disease (AD)-like symptoms induced by the amyloid-b protein (Ab) in a rat model. 6-Gingerol is the major gingerol in ginger rhizomes, but its effect on the treatment of AD remains unclear. In this study, we aimed to determine if 6-gingerol had a protective effect on Ab 1-42 -induced damage and apoptotic death in rat pheochromocytoma cells (PC12 cells) and to investigate the underlying mechanisms by which 6-gingerol may exert its neuroprotective effects. Our results indicated that pre-treatment with 6-gingerol significantly increased cell viability and reduced cell apoptosis in Ab 1-42 -treated cells. Moreover, 6-gingerol pretreatment markedly reduced the level of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA), the production of nitric oxide (NO), and the leakage of lactate dehydrogenase (LDH) and increased superoxide dismutase (SOD) activity compared with the Ab 1-42 treatment group. In addition, 6-gingerol pretreatment also significantly enhanced the protein levels of phosphorylated Akt (p-Akt) and glycogen synthase kinase-3b (p-GSK-3b). Overall, these results indicate that 6-gingerol exhibited protective effects on apoptosis induced by Ab 1-42 in cultured PC12 cells by reducing oxidative stress and inflammatory responses, suppressing the activation of GSK-3b and enhancing the activation of Akt, thereby exerting neuroprotective effects. Therefore, 6-gingerol may be useful in the prevention and/or treatment of AD.

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Section: Discussionmentioning

confidence: 99%

The Role of 6-Gingerol on Inhibiting Amyloid β Protein-Induced Apoptosis in PC12 Cells

Zeng

Zong

Zhang

et al. 2015

Rejuvenation Research

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“…Based on the fact that A␤ deposits in senile plaques, Hardy first proposed the hypothesis of amyloid cascade, which states that the accumulated A␤ causes neuronal cell damage and death, resulting in the incidence of AD [2]. Recently, more and more evidence indicates that oligomeric A␤ causes tau hyperphosphorylation, synaptic loss, and neuronal apoptosis in vitro and in vivo [3][4][5][6][7]. The mechanism that A␤ induces cell apoptosis, however, is still not well understood.…”

Section: Introductionmentioning

confidence: 98%

Curcumin-Mediated Neuroprotection Against Amyloid-β-Induced Mitochondrial Dysfunction Involves the Inhibition of GSK-3β

Huang

Jiang

2012

JAD

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The deposition of amyloid-β (Aβ) peptides in senile plaques is one of pathological hallmarks of Alzheimer's disease (AD). Mitochondrial dysfunction is an early event of cell apoptosis. Increasing evidence indicates that Aβ induces neuronal apoptosis through mitochondrial dysfunction. Curcumin, an anti-oxidative component of turmeric (Curcuma longa), has shown anti-tumor, anti-inflammatory, and anti-oxidative properties. In this study, we investigated the protective effects of curcumin against mitochondrial dysfunction induced by Aβ. Based on the assay results of mitochondrial metabolic markers, we found that curcumin protects human neuroblastoma SH-SY5Y cells against the Aβ-induced damage of mitochondrial energy metabolism. Curcumin inhibits Aβ-induced mitochondrial depolarization of membrane potential (Δψm) and suppresses mitochondrial apoptosis-related proteins including cytochrome c, caspase-3, and Bax, which are activated by Aβ. Aβ-induced disturbances of redox state are linked to mitochondrial dysfunction. Curcumin normalizes cellular antioxidant enzymes (including SOD and catalase) in both protein expression and activity and decreases oxidative stress level in Aβ-treated cells. Both total GSK-3β expression and phospho-Ser9 GSK-3β (pSer9-GSK-3β) are down-regulated in the cells pre-treated with curcumin. This study demonstrates curcumin-mediated neuroprotection against Aβ-induced mitochondrial metabolic deficiency and abnormal alteration of oxidative stress. Inhibition of GSK-3β is involved in the protection of curcumin against Aβ-induced mitochondrial dysfunction.

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“…Reactive oxygen species (ROS) production and activation of c-Jun N -terminal kinases (JNKs) are involved in many pathological mechanisms in AD [3]. Apoptosis signal-regulating kinase 1 (ASK1) is a protein kinase of the mitogen-activated protein kinase kinase kinase (MAPKKK) family that activates the JNK and p38 MAPK signaling cascades [4,5].…”

Section: Introductionmentioning

confidence: 99%

Apoptosis Signal Regulating Kinase 1 (ASK1): Potential as a Therapeutic Target for Alzheimer’s Disease

Song

Park

Lee

et al. 2014

IJMS

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Alzheimer’s disease (AD) is the most common form of dementia, characterized by a decline in memory and cognitive function. Clinical manifestations of AD are closely associated with the formation of senile plaques and neurofibrillary tangles, neuronal loss and cognitive decline. Apoptosis signal regulating kinase 1 (ASK1) is a mediator of the MAPK pathway, which regulates various cellular responses such as apoptosis, cell survival, and differentiation. Accumulating evidence indicates that ASK1 plays a key role in the pathogenesis of neurodegenerative disorders such as Huntington’s disease and AD. Of particular interest, ASK1 is associated with many signaling pathways, which include endoplasmic reticulum (ER) stress-mediated apoptosis, Aβ-induced neurotoxicity, tau protein phosphorylation, and insulin signal transduction. Here, we review experimental evidence that links ASK1 signaling and AD pathogenesis and propose that ASK1 might be a new point of therapeutic intervention to prevent or treat AD.

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Neuron Specific Toxicity of Oligomeric Amyloid-β: Role for JUN-Kinase and Oxidative Stress

Cited by 50 publications

References 33 publications

The Role of 6-Gingerol on Inhibiting Amyloid β Protein-Induced Apoptosis in PC12 Cells

The Role of 6-Gingerol on Inhibiting Amyloid β Protein-Induced Apoptosis in PC12 Cells

Curcumin-Mediated Neuroprotection Against Amyloid-β-Induced Mitochondrial Dysfunction Involves the Inhibition of GSK-3β

Apoptosis Signal Regulating Kinase 1 (ASK1): Potential as a Therapeutic Target for Alzheimer’s Disease

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