scholarly journals Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death

2004 ◽  
Vol 165 (3) ◽  
pp. 347-356 ◽  
Author(s):  
Junichi Hitomi ◽  
Taiichi Katayama ◽  
Yutaka Eguchi ◽  
Takashi Kudo ◽  
Manabu Taniguchi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Amyloid Β ◽  
Small Interfering Rnas ◽  
Caspase 12 ◽  
Induced Apoptosis ◽  
Interfering Rna ◽  
Human Caspase

Recent studies have suggested that neuronal death in Alzheimer's disease or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Although caspase-12 has been implicated in ER stress-induced apoptosis and amyloid-β (Aβ)–induced apoptosis in rodents, it is controversial whether similar mechanisms operate in humans. We found that human caspase-4, a member of caspase-1 subfamily that includes caspase-12, is localized to the ER membrane, and is cleaved when cells are treated with ER stress-inducing reagents, but not with other apoptotic reagents. Cleavage of caspase-4 is not affected by overexpression of Bcl-2, which prevents signal transduction on the mitochondria, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Furthermore, a reduction of caspase-4 expression by small interfering RNA decreases ER stress-induced apoptosis in some cell lines, but not other ER stress-independent apoptosis. Caspase-4 is also cleaved by administration of Aβ, and Aβ-induced apoptosis is reduced by small interfering RNAs to caspase-4. Thus, caspase-4 can function as an ER stress-specific caspase in humans, and may be involved in pathogenesis of Alzheimer's disease.

scholarly journals Neuroprotective effects of verbascoside against Alzheimer’s disease via the relief of endoplasmic reticulum stress in Aβ-exposed U251 cells and APP/PS1 mice

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Chunyue Wang ◽  
Xueying Cai ◽  
Ruochen Wang ◽  
Siyu Zhai ◽  
Yongfeng Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Amyloid Β ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Morris Water Maze Test ◽  
Proteomics Analysis ◽  
Neuroprotective Effects ◽  
U251 Cells

Abstract Background Endoplasmic reticulum (ER) stress is involved in the progression of Alzheimer’s disease (AD). Verbascoside (VB), an active phenylethanoid glycoside that was first isolated from Verbascum sinuatum (the wavyleaf mullein), possesses anti-inflammatory, antioxidative, and anti-apoptotic effects. The purpose of this study was to elucidate the beneficial effects of VB in amyloid β (Aβ)1–42-damaged human glioma (U251) cells and in APPswe/PSEN1dE9 transgenic (APP/PS1) mice. Methods U251 cells were co-incubated with 10 μM of Aβ1-42 and treated with VB. The protective effects of VB were investigated by using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay, flow cytometry, fluorescence staining, and transmission electron microscopy. APP/PS1 transgenic mice were treated for 6 weeks with VB. Learning and memory were evaluated using a Morris water maze test. Immunohistochemistry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, thioflavin-S staining, and proteomics analysis were performed to study the potential neuroprotective mechanism. Enzyme-linked immunosorbent assays and western blot were performed to analyze altered protein levels of brain lysates in APP/PS1 mice and/or Aβ1-42-damaged U251 cells. Results In Aβ1-42-damaged U251 cells, VB significantly improved cell viability, inhibited apoptosis, reduced calcium accumulation and the intracellular concentrations of reactive oxygen species, and improved the morphology of mitochondria and ER. In APP/PS1 mice, 6-week administration of VB significantly improved memory and cognition. VB inhibited apoptosis, reduced the deposition of Aβ, reduced the formation of neurofibrillary tangles formed by hyperphosphorylated tau protein, and downregulated the expression levels of 4-hydroxynonenal and mesencephalic astrocyte-derived neurotrophic factor in the brains of APP/PS1 mice. Proteomics analysis of mouse hippocampus suggested that the neuroprotective effect of VB may be related to the reduction of ER stress. This was indicated by the fact that VB inhibited the three branches of the unfolded protein response, thereby attenuating ER stress and preventing apoptosis. Conclusions The results confirmed that VB possesses significant neuroprotective effects, which are related to the reduction of ER stress. These findings support the status of VB as a potentially effective treatment for AD and warrant further research.

scholarly journals Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease

Aging Cell ◽  
2013 ◽  
Vol 12 (2) ◽  
pp. 292-302 ◽  
Author(s):  
Elena Alberdi ◽  
Ane Wyssenbach ◽  
María Alberdi ◽  
Mª V. Sánchez-Gómez ◽  
Fabio Cavaliere ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Amyloid Β ◽  
Model Of Alzheimer’S Disease

scholarly journals Intracellular Accumulation of Toxic Turn Amyloid-β is Associated with Endoplasmic Reticulum Stress in Alzheimer's Disease

2013 ◽  
Vol 10 (1) ◽  
pp. 11-20 ◽  
Author(s):  
Naoko Soejima ◽  
Yasumasa Ohyagi ◽  
Norimichi Nakamura ◽  
Eri Himeno ◽  
Kyoko M. Iinuma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Amyloid Β ◽  
Intracellular Accumulation

scholarly journals Possible involvement of endoplasmic reticulum stress in the pathogenesis of Alzheimer’s disease

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Toru Hosoi ◽  
Jun Nomura ◽  
Koichiro Ozawa ◽  
Akinori Nishi ◽  
Yasuyuki Nomura
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Quality ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe endoplasmic reticulum (ER) is an organelle that plays a crucial role in protein quality control such as protein folding. Evidence to indicate the involvement of ER in maintaining cellular homeostasis is increasing. However, when cells are exposed to stressful conditions, which perturb ER function, unfolded proteins accumulate leading to ER stress. Cells then activate the unfolded protein response (UPR) to cope with this stressful condition. In the present review, we will discuss and summarize recent advances in research on the basic mechanisms of the UPR. We also discuss the possible involvement of ER stress in the pathogenesis of Alzheimer’s disease (AD). Potential therapeutic opportunities for diseases targeting ER stress is also described.

scholarly journals Intracellular Accumulation of Toxic Turn Amyloid-β is Associated with Endoplasmic Reticulum Stress in Alzheimer’s Disease

2013 ◽  
Vol 10 (1) ◽  
pp. 11-20 ◽  
Author(s):  
Naoko Soejima ◽  
Yasumasa Ohyagi ◽  
Norimichi Nakamura ◽  
Eri Himeno ◽  
Kyoko M. Iinuma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Amyloid Β ◽  
Intracellular Accumulation

ER Stress Signaling in Alzheimer's Disease

2020 ◽  
pp. 180-211
Author(s):  
Md. Motiar Rahman ◽  
Looniva Shrestha ◽  
Mst Ara Gulshan
Keyword(s):  
Public Health ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Stress Signaling ◽  
Novel Therapies ◽  
Er Stress Response ◽  
Health Related ◽  
Common Etiology

Alzheimer's disease (AD) is the most common etiology of dementia amongst aged individuals and a principal public health-related abnormality. It is considered as a multifactorial disorder, with no particular origin identified, and also some modifiable, as well as non-modifiable threats are correlated with its progression and development. The endoplasmic reticulum (ER) stress response is considered as a key process in the pathogenesis of AD. In this chapter, the authors present a summary of related transmembrane kinase proteins responsible for the onset of AD as well as show the interrelationship between ER stress and AD. Finally, the authors demonstrate the therapeutics intervention for AD diagnosis by highlighting the current practices to advance novel therapies.

scholarly journals The role of the Amyloid Precursor Protein mutations and PERKdependent signaling pathways in the pathogenesis of Alzheimer’s disease

2016 ◽  
Vol 12 ◽  
pp. 48-59 ◽  
Author(s):  
Wioletta Rozpędek ◽  
Alicja Nowak ◽  
Dariusz Pytel ◽  
Dawid Lewko ◽  
J. Alan Diehl ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Signaling Pathways ◽  
Senile Plaques ◽  
B Cell Lymphoma ◽  
Stress Conditions ◽  
Chromosome 21 ◽  
Age Related

Alzheimer’s disease (AD) is a highly complex, progressive, age-related neurodegenerative human disease entity. The genetic basis of AD is strictly connected with occurrence of mutations in Amyloid Precursor (APP) gene on chromosome 21. Molecular mechanism that leads to AD development still remains unclear. Recent data reported that it is closely correlated with Endoplasmic Reticulum (ER) stress conditions, which subsequently activate Unfolded Protein Response (UPR) signaling pathways, via the induction of protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a self-protective, adaptive response to adverse stress conditions. That results in the attenuation of global protein synthesis and, on the contrary, selective translation of Activating Transcriptor Factor 4 (ATF4) and secretase β. Interestingly, under prolonged, severe ER stress UPR may switch its signal into apoptotic cell death. That ensues by ATF4-CHOP-mediated activation of a range of pro-apoptotic genes and, on the other hand, downregulation of the expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) genes. Current investigations suggest that inhibitions of PERK activity may contribute to the attenuation of the deposition of toxic senile plaques in the brain tissue and, as a result, prevent degeneration of neurons and decline in cognitive abilities.

scholarly journals Baicalein Induces Apoptosis and Autophagy via Endoplasmic Reticulum Stress in Hepatocellular Carcinoma Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Zhongxia Wang ◽  
Chunping Jiang ◽  
Weibo Chen ◽  
Guang Zhang ◽  
Dongjun Luo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Intracellular Calcium ◽  
Water Soluble ◽  
Small Interfering Rnas ◽  
Therapeutic Drugs ◽  
Induced Apoptosis ◽  
Hcc Cells

Background. Hepatocellular carcinoma (HCC) remains a disastrous disease and the treatment for HCC is rather limited. Separation and identification of active compounds from traditionally used herbs in HCC treatment may shed light on novel therapeutic drugs for HCC.Methods. Cell viability and colony forming assay were conducted to determine anti-HCC activity. Morphology of cells and activity of caspases were analyzed. Antiapoptotic Bcl-2 family proteins and JNK were also examined. Levels of unfolded protein response (UPR) markers were determined and intracellular calcium was assayed. Small interfering RNAs (siRNAs) were used to investigate the role of UPR and autophagy in baicalein-induced cell death.Results. Among four studied flavonoids, only baicalein exhibited satisfactory inhibition of viability and colony formation of HCC cells within water-soluble concentration. Baicalein induced apoptosis via endoplasmic reticulum (ER) stress, possibly by downregulating prosurvival Bcl-2 family, increasing intracellular calcium, and activating JNK. CHOP was the executor of cell death during baicalein-induced ER stress while eIF2αand IRE1αplayed protective roles. Protective autophagy was also triggered by baicalein in HCC cells.Conclusion. Baicalein exhibits prominent anti-HCC activity. This flavonoid induces apoptosis and protective autophagy via ER stress. Combination of baicalein and autophagy inhibitors may represent a promising therapy against HCC.

scholarly journals Critical review: involvement of endoplasmic reticulum stress in the aetiology of Alzheimer's disease

Open Biology ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 180024 ◽  
Author(s):  
Shoko Hashimoto ◽  
Takaomi C. Saido
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Mouse Models ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Er Stress Response

The endoplasmic reticulum (ER) stress response is regarded as an important process in the aetiology of Alzheimer's disease (AD). The accumulation of pathogenic misfolded proteins and the disruption of intracellular calcium (Ca 2+ ) signalling are considered to be fundamental mechanisms that underlie the induction of ER stress, leading to neuronal cell death. Indeed, a number of studies have proposed molecular mechanisms linking ER stress to AD pathogenesis based on results from in vitro systems and AD mouse models. However, stress responsivity was largely different between each mouse model, even though all of these models display AD-related pathologies. While several reports have shown elevated ER stress responses in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (Tg) AD mouse models, we and other groups, in contrast, observed no such ER stress response in APP-single-Tg or App -knockin mice. Therefore, it is debatable whether the ER stress observed in APP and PS1 double-Tg mice is due to AD pathology. From these findings, the roles of ER stress in AD pathogenesis needs to be carefully addressed in future studies. In this review, we summarize research detailing the relationship between ER stress and AD, and analyse the results in detail.

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