Thiamine deficiency induces endoplasmic reticulum stress in neurons

Wang, Xin; Wang, Bingwei; Fan, Zhiqin; Shi, Xianglin; Zhang, Ke; Luo, Jia

doi:10.1016/j.neuroscience.2006.10.008

Cited by 89 publications

(106 citation statements)

References 58 publications

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“…TD induces ER stress in thalamus [54]. Electron microscopy also reveals differences in brain ER: enlarged lumens, deposition of vesicles and an irregular packing pattern of rough ER [54]. Thus, TD may induce a general problem in protein processing.…”

Section: Discussionmentioning

confidence: 95%

“…Recent results suggest that TD triggers apoptosis by activating caspase-3 mediated signaling pathway which leads to neuronal loss [15]. Also, TD induces endoplasmic reticulum (ER) stress in neurons and blocking the activation of caspase-12, an ER-anchored caspase, alleviates TD-induced neuronal death [54]. Although, these changes are largely restricted to the areas with neuron death, the studies were not done in plaque competent mice.…”

Section: Discussionmentioning

confidence: 99%

“…However, only TNFα is altered in cortex [34]. In addition, TD induces endoplasmic reticulum (ER) stress in a region specific manner suggesting that altered processing of proteins is occurring [54]. TD also includes multiple behavioral deficits including memory deficits and changes in motor performance that are due to central cholinergic deficits [24].…”

Section: Introductionmentioning

confidence: 99%

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Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

Karuppagounder

Shi

et al. 2009

Neurobiology of Aging

121

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Mitochondrial dysfunction, oxidative stress and reductions in thiamine-dependent enzymes have been implicated in multiple neurological disorders including Alzheimer's disease (AD). Experimental thiamine deficiency (TD) is an established model for reducing the activities of thiamine-dependent enzymes in brain. TD diminishes thiamine dependent enzymes throughout the brain, but produces a time-dependent selective neuronal loss, glial activation, inflammation, abnormalities in oxidative metabolism and clusters of degenerating neurites in only specific thalamic regions. The present studies tested how TD alters brain pathology in Tg19959 transgenic mice over expressing a double mutant form of the amyloid precursor protein (APP). TD exacerbated amyloid plaque pathology in transgenic mice and enlarged the area occupied by plaques in cortex, hippocampus and thalamus by 50%, 200% and 200%, respectively. TD increased Aβ 1-42 levels by about three-fold, β-CTF (C99) levels by 33% and β-secretase (BACE1) protein levels by 43%. TD induced inflammation in areas of plaque formation. Thus, the induction of mild impairment of oxidative metabolism, oxidative stress and inflammation induced by TD alters metabolism of APP and/or Aβ and promotes accumulation of plaques independent of neuron loss or neuritic clusters.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

Karuppagounder

Shi

et al. 2009

Neurobiology of Aging

121

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“…36) Selective cell death is common in many agingrelated neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and progressive supranuclear palsy. 37) The neurological disorder that is most clearly associated with TD in humans is Wernicke-Korsakoff syndrome, which is characterized by severe memory loss, cholinergic deficits and selective cell death in specific brain regions. These feature of the TD model are thought to be suitable for investigating the cellular mechanism of neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Effects of Yokukansan, a Traditional Japanese Medicine, on Memory Disturbance and Behavioral and Psychological Symptoms of Dementia in Thiamine-Deficient Rats

Ikarashi

Iizuka

Imamura

et al. 2009

Biological & Pharmaceutical Bulletin

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Behavioral and psychological symptoms of dementia (BPSD), including anxiety, depression, excitement, anger, hallucination, and roaming, are seen in patients with Alzheimer's disease and other forms of senile dementia. 1,2) To date, although atypical or conventional antipsychotic medications are used to treat BPSD, drug-induced extrapyramidal symptoms and other adverse events are seen. In addition, the Food and Drug Administration warned in 2005 that the antipsychotic medications increase mortality among elderly patients. Therefore, new remedies without adverse effects have been sought.Yokukansan (TJ-54) is a traditional herbal medicine called a 'kampo medicine' in Japan. The Ministry of Health, Labor and Welfare in Japan has approved it as a remedy for neurosis, insomnia, and irritability in children. Recently, TJ-54 has been reported to ameliorate excitement, anger, and hallucination in BPSD in patients with Alzheimer's disease, dementia with Lewy bodies, and other forms of senile dementia. 1,2) However, there is limited research on this compound and the mechanism by which it alters the symptoms of dementia is unknown.Up to now, various dementia models including b-amyloid protein precursor (APP) 3) or a-synuclein transgenic mice, 4) and ischemia 5) or scopolamine 6) -treated animals have been used for research in the pathogenesis and therapy of dementia. However, because most studies focused on deficits of the functions of learning and memory that are the main symptoms of dementia, or because only the abnormalities of learning and memory functions are observed in the most models, information regarding BPSD was few in the animal models. Thus, animal models covering peripheral symptoms like BPSD observed in patients with dementia have little been reported. However, recently, it has been reported that not only impairment of learning and memory but also BPSD-like behaviors such as anxiety, depression, muricide, attacking, and startle responses are observed in thiamine-deficient (TD) rats and mice, 7) i.e., the data about BPSD-like behaviors are more abundant than other dementia models. TD is a critical factor in the etiology of Wernicke-Korsakoff's syndrome, which is characterized by a decrease in thiamine pyrophosphate (biologically active form of thiamine)-dependent enzymes involved in cellular glucose and energy metabolism in the brain.8) Thus, although the pathogenesis (or an induction factor) in each dementia model including TD animals is different, there is a common point that memory dysfunction is observed in each model. Furthermore, similar deficiencies in thiamine pyrophosphate-dependent enzyme activities are reported in postmortem brain tissues of patients with Alzheimer's disease. 9) TD has been also reported to induce selective neuronal loss, 10) cholinergic deficits, 11) and accumulations of the abnormal tau isoforms 12) and APP 13) that are involved in Alzheimer's disease. These findings suggest that TD animals may be a valuable tool for evaluation of pharmacotherapy for BPSD as well as dysfunction ...

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“…For example, gene expression and protein level of endothelial nitric oxide synthase (eNOS) increase in regions that are vulnerable to TD at symptomatic stages of TD (Kruse et al, 2004). An early response of endoplasmic reticulum to TD occurs by day 6 of TD (Wang et al, 2007). The up-regulation of markers for endoplasmic reticulum stress precedes eNOS induction and neuropathological lesion.…”

Section: Discussionmentioning

confidence: 99%

Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability

Shi

Karuppagounder

et al. 2007

Neurochemistry International

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Thiamine-dependent enzymes are diminished in multiple neurodegenerative diseases. Thiamine deficiency (TD) reduces the activity of thiamine dependent-enzymes [e.g., the α-ketoglutarate dehydrogenase complex (KGDHC)], induces regional selective neurodegeneration and serves as a model of a mild impairment of oxidative metabolism. The current experiments tested whether changes in KGDHC protein subunits (E1k, E2k and E3) or activity or message levels underlie the selective loss of neurons in particular brain regions. Thus, TD-induced changes in these variables in the brain region most vulnerable to TD [the sub-medial thalamic nucleus (SmTN)] were compared to those in a region that is relatively resistant to TD (cortex) at stages of TD when the neuron loss in SmTN is not present, minimal or severe. Impaired motor performance on rotarod was apparent by 8 days of TD (-32%) and was severe by 10 days of TD (-97%). At TD10, the overall KGDHC activity measured by an in situ histochemical staining method declined 52% in SmTN but only 20% in cortex. Reductions in the E2k and E3 mRNA in SmTN occurred as early as TD6 (-28% and -18%, respectively) and were more severe by TD10 (-61% and -66%, respectively). On the other hand, the level of E1k mRNA did not decline in SmTN until TD10 (-48%). In contrast, TD did not alter mRNA levels of the subunits in cortex at late stages. Western blots and immunocytochemistry revealed different aspects of the changes in protein levels. In SmTN, the immunoreactivity of E1k and E3 by Western blotting increased 34% and 40%, respectively, only at TD8. In cortex, the immunoreactivity of the three subunits was not altered. Immunocytochemical staining of brain sections from TD10 mice indicated a reduction in the immunoreactivity of all subunits in SmTN, but not in cortex. These findings demonstrate that the response of the KGDHC activity, mRNA and immunoreactivity of E1k, E2k and E3 to TD is region-and time-dependent. Loss of KGDHC activity in cortex is likely related to post-translational modification rather than a loss of protein, whereas in SmTN transcriptional and post-translational modifications may account for diminished KGDHC activity. Moreover, the earlier detection in TD induced-changes of the transcripts of KGDHC indicates that transcriptional modification of the two subunits (E2k and E3) of KGDHC may be one of the early events in the cascade leading to selective neuronal death.

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Thiamine deficiency induces endoplasmic reticulum stress in neurons

Cited by 89 publications

References 58 publications

Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

Effects of Yokukansan, a Traditional Japanese Medicine, on Memory Disturbance and Behavioral and Psychological Symptoms of Dementia in Thiamine-Deficient Rats

Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability

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