Thymoquinone protects cultured hippocampal and human induced pluripotent stem cells-derived neurons against α-synuclein-induced synapse damage

Alhebshi, A.H.; Odawara, Aoi; Gotoh, Masao; Suzuki, Ikurou

doi:10.1016/j.neulet.2013.09.049

Cited by 54 publications

(34 citation statements)

References 28 publications

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“…iCell neurons exhibited toxicity to α-synuclein and were used as an in vitro PD model. The potential neuroprotective effect of thymoquinone (TQ) on α-synuclein-induced alteration in synapse density, synaptic vesicle recycling and electrical activity was assessed in iCell neurons (Alhebshi et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

Wang

Frank

et al. 2017

Toxicology and Applied Pharmacology

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Thiamine (vitamin B1) deficiency (TD) plays a major role in the etiology of Wernicke's encephalopathy (WE) which is a severe neurological disorder. TD induces selective neuronal cell death, neuroinflammation, endoplasmic reticulum (ER) stress and oxidative stress in the brain which are commonly observed in many aging-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and progressive supranuclear palsy (PSP). However, the underlying cellular and molecular mechanisms remain unclear. The progress in this line of research is hindered due to the lack of appropriate in vitro models. The neurons derived for the human induced pluripotent stem cells (hiPSCs) provide a relevant and powerful tool for the research in pharmaceutical and environmental neurotoxicity. In this study, we for the first time used human induced pluripotent stem cells (hiPSCs)-derived neurons (iCell neurons) to investigate the mechanisms of TD-induced neurodegeneration. We showed that TD caused a concentration- and duration-dependent death of iCell neurons. TD induced ER stress which was evident by the increase in ER stress markers, such as GRP78, XBP-1, CHOP, ATF-6, phosphorylated eIF2α, and cleaved caspase-12. TD also triggered oxidative stress which was shown by the increase in the expression 2,4-dinitrophenyl (DNP) and 4-hydroxynonenal (HNE). ER stress inhibitors (STF-083010 and salubrinal) and antioxidant N-acetyl cysteine (NAC) were effective in alleviating TD-induced death of iCell neurons, supporting the involvement of ER stress and oxidative stress. It establishes that the iCell neurons are a novel tool to investigate cellular and molecular mechanisms for TD-induced neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

Wang

Frank

et al. 2017

Toxicology and Applied Pharmacology

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“…Fibroblasts from healthy male individuals were reprogramed and differentiated into iCell neurons. These neurons were previously characterized as cortical forebrain human neurons (Haythornthwaite et al, 2012;Xu et al, 2013;Alhebshi et al, 2014;Dage et al, 2014). The cells were seeded on plates precoated with poly-D-lysine and laminin following CDI protocol.…”

Section: Methodsmentioning

confidence: 99%

“…These data confirmed that tau oligomers can induce aggregation of insoluble, hyperphosphorylated tau species in hiPSC neurons. Numerous reports have demonstrated that autophagy is a major process involved in the clearance of intracellular tau aggregates in various in vitro and in vivo models of tau pathology (Berger et al, 2006;Frederick et al, 2015;Friedman et al, 2015). Rapamycin is a well known activator of autophagy (Berger et al, 2006).…”

Section: Internalized Tau Oligomer Seeds But Not Monomer Seeds Inducementioning

confidence: 99%

“…Numerous reports have demonstrated that autophagy is a major process involved in the clearance of intracellular tau aggregates in various in vitro and in vivo models of tau pathology (Berger et al, 2006;Frederick et al, 2015;Friedman et al, 2015). Rapamycin is a well known activator of autophagy (Berger et al, 2006). We examined the effect of rapamycin (100 nM) by adding it to neurons 24 h before seeding with tau oligomers.…”

Section: Internalized Tau Oligomer Seeds But Not Monomer Seeds Inducementioning

confidence: 99%

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Internalized Tau Oligomers Cause Neurodegeneration by Inducing Accumulation of Pathogenic Tau in Human Neurons Derived from Induced Pluripotent Stem Cells

et al. 2015

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Neuronal inclusions of hyperphosphorylated and aggregated tau protein are a pathological hallmark of several neurodegenerative tauopathies, including Alzheimer's disease (AD). The hypothesis of tau transmission in AD has emerged from histopathological studies of the spatial and temporal progression of tau pathology in postmortem patient brains. Increasing evidence in cellular and animal models supports the phenomenon of intercellular spreading of tau. However, the molecular and cellular mechanisms of pathogenic tau transmission remain unknown. The studies described herein investigate tau pathology propagation using human neurons derived from induced pluripotent stem cells. Neurons were seeded with full-length human tau monomers and oligomers and chronic effects on neuronal viability and function were examined over time. Tau oligomer-treated neurons exhibited an increase in aggregated and phosphorylated pathological tau. These effects were associated with neurite retraction, loss of synapses, aberrant calcium homeostasis, and imbalanced neurotransmitter release. In contrast, tau monomer treatment did not produce any measureable changes. This work supports the hypothesis that tau oligomers are toxic species that can drive the spread of tau pathology and neurodegeneration.

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“…On the other hand, knock down of Pink1 could potentially be used to evaluate PD-related mitochondrial dysfunction (Seibler et al, 2011). Finally, acute neurotoxicity could be assessed using amyloid or Alpha-synuclein addition to control neurons (Xu et al, 2013;Alhebshi et al, 2014). All of these examples suggest that iCell Ò neurons are suitable for to create a disease model if the phenotype of interest is observed within a short timeframe.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of established human iPSC-derived neurons to model neurodegenerative diseases

et al. 2015

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Thymoquinone protects cultured hippocampal and human induced pluripotent stem cells-derived neurons against α-synuclein-induced synapse damage

Cited by 54 publications

References 28 publications

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

Internalized Tau Oligomers Cause Neurodegeneration by Inducing Accumulation of Pathogenic Tau in Human Neurons Derived from Induced Pluripotent Stem Cells

Evaluation of established human iPSC-derived neurons to model neurodegenerative diseases

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