scholarly journals Upregulation of the Sarco-Endoplasmic Reticulum Calcium ATPase 1 Truncated Isoform Plays a Pathogenic Role in Alzheimer’s Disease

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1539 ◽  
Author(s):  
Bussiere ◽  
Oulès ◽  
Mary ◽  
Vaillant-Beuchot ◽  
Martin ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Human Neuroblastoma ◽  
Endoplasmic Reticulum Calcium ◽  
Protein Levels ◽  
Functional Consequences ◽  
Β Amyloid

Dysregulation of the Endoplasmic Reticulum (ER) Ca2+ homeostasis and subsequent ER stress activation occur in Alzheimer Disease (AD). We studied the contribution of the human truncated isoform of the sarco-endoplasmic reticulum Ca2+ ATPase 1 (S1T) to AD. We examined S1T expression in human AD-affected brains and its functional consequences in cellular and transgenic mice AD models. S1T expression is increased in sporadic AD brains and correlates with amyloid β (Aβ) and ER stress chaperone protein levels. Increased S1T expression was also observed in human neuroblastoma cells expressing Swedish-mutated β-amyloid precursor protein (βAPP) or treated with Aβ oligomers. Lentiviral overexpression of S1T enhances in return the production of APP C-terminal fragments and Aβ through specific increases of β-secretase expression and activity, and triggers neuroinflammation. We describe a molecular interplay between S1T-dependent ER Ca2+ leak, ER stress and βAPP-derived fragments that could contribute to AD setting and/or progression.

scholarly journals A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer’s disease

2021 ◽  
Author(s):  
Vega García-Escudero ◽  
Daniel Ruiz-Gabarre ◽  
Ricardo Gargini ◽  
Mar Pérez ◽  
Esther García ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Rna Seq ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
Post Translational Modifications ◽  
Protein Levels ◽  
Tau Isoform ◽  
Human Specific

AbstractTauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer’s patients’ brains (Braak I n = 3; Braak II n = 6, Braak III n = 3, Braak IV n = 1, and Braak V n = 10, Braak VI n = 8) with respect to non-demented control subjects (n = 9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3β, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer’s disease and other tauopathies.

scholarly journals Maternal high-fat diet induces metabolic stress response disorders in offspring hypothalamus

2017 ◽  
Vol 59 (1) ◽  
pp. 81-92 ◽  
Author(s):  
Long The Nguyen ◽  
Sonia Saad ◽  
Yi Tan ◽  
Carol Pollock ◽  
Hui Chen
Keyword(s):  
Endoplasmic Reticulum ◽  
Body Weight ◽  
Er Stress ◽  
High Fat Diet ◽  
Maternal Obesity ◽  
Mrna Level ◽  
Metabolic Stress ◽  
High Fat ◽  
Chemical Chaperone ◽  
Protein Levels

Maternal obesity has been shown to increase the risk of obesity and related disorders in the offspring, which has been partially attributed to changes of appetite regulators in the offspring hypothalamus. On the other hand, endoplasmic reticulum (ER) stress and autophagy have been implicated in hypothalamic neuropeptide dysregulation, thus may also play important roles in such transgenerational effect. In this study, we show that offspring born to high-fat diet-fed dams showed significantly increased body weight and glucose intolerance, adiposity and plasma triglyceride level at weaning. Hypothalamic mRNA level of the orexigenic neuropeptide Y (NPY) was increased, while the levels of the anorexigenic pro-opiomelanocortin (POMC), NPY1 receptor (NPY1R) and melanocortin-4 receptor (MC4R) were significantly downregulated. In association, the expression of unfolded protein response (UPR) markers including glucose-regulated protein (GRP)94 and endoplasmic reticulum DNA J domain-containing protein (Erdj)4 was reduced. By contrast, protein levels of autophagy-related genes Atg5 and Atg7, as well as mitophagy marker Parkin, were slightly increased. The administration of 4-phenyl butyrate (PBA), a chemical chaperone of protein folding and UPR activator, in the offspring from postnatal day 4 significantly reduced their body weight, fat deposition, which were in association with increased activating transcription factor (ATF)4, immunoglobulin-binding protein (BiP) and Erdj4 mRNA as well as reduced Parkin, PTEN-induced putative kinase (PINK)1 and dynamin-related protein (Drp)1 protein expression levels. These results suggest that hypothalamic ER stress and mitophagy are among the regulatory factors of offspring metabolic changes due to maternal obesity.

Inhibition of miR-96-5p May Reduce Aβ 42/Aβ40 Ratio via Regulating ATP-Binding Cassette A1

2021 ◽  
pp. 1-11
Author(s):  
Min Zhu ◽  
Longfei Jia ◽  
Jianping Jia
Keyword(s):  
Amyloid Β ◽  
Luciferase Assay ◽  
Atp Binding ◽  
Aβ Oligomers ◽  
Dual Luciferase Assay ◽  
Protein Levels ◽  
Qrt Pcr ◽  
Polymerase Chain ◽  
5Xfad Mice ◽  
Atp Binding Cassette

Background: Imbalance between amyloid-β (Aβ) production and clearance results in Aβ accumulation. Regulating Aβ levels is still a hot point in the research of Alzheimer’s disease (AD). Objective: To identify the differential expression of ATP-binding cassette A1 (ABCA1) and its upstream microRNA (miRNA) in AD models, and to explore their relationships with Aβ levels. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to determine the expression of ABCA1 in 5xFAD mice, SH-SY5Y cells treated with Aβ oligomers and SH-SY5YAβPP695 cells (AD models). TargetScan was used to predict the upstream miRNAs for ABCA1. Dual-luciferase assay was conducted to identify the regulation of the miRNA on ABCA1. qRT-PCR was used to measure the expression of miRNA in AD models. Finally, enzyme-linked immunosorbent assays were performed to detect Aβ 42 and Aβ40 levels. Results: The expression of ABCA1 was significantly down regulated in AD models at both mRNA and protein levels. Dual-luciferase assay showed that miR-96-5p could regulate the expression of ABCA1 through binding to the 3 untranslated region of ABCA1. The level of miR-96-5p was significantly elevated in AD models. The expression of ABCA1 was enhanced while Aβ 42 levels and Aβ 42/Aβ 40 ratios were reduced in SH-SY5Y A βPP695 cells after treated with miR-96-5p inhibitor. Conclusion: The current study found that miR-96-5p is the upstream miRNA for ABCA1. Suppression of miR-96-5p in AD models could reduce Aβ 42/Aβ 40 ratios via up regulating the expression of ABCA1, indicating that miR-96-5p plays an important role in regulating the content of Aβ.

Tissue transglutaminase and apoptosis: sense and antisense transfection studies with human neuroblastoma cells

1994 ◽  
Vol 14 (10) ◽  
pp. 6584-6596
Author(s):  
G Melino ◽  
M Annicchiarico-Petruzzelli ◽  
L Piredda ◽  
E Candi ◽  
V Gentile ◽  
...  
Keyword(s):  
Cell Death ◽  
Structural Changes ◽  
Tissue Transglutaminase ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Neuroblastoma Cell Line ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Transfected Cells ◽  
Protein Levels

In this report, we show that the overexpression of tissue transglutaminase (tTG) in the human neuroblastoma cell line SK-N-BE(2) renders these neural crest-derived cells highly susceptible to death by apoptosis. Cells transfected with a full-length tTG cDNA, under the control of a constitutive promoter, show a drastic reduction in proliferative capacity paralleled by a large increase in cell death rate. The dying tTG-transfected cells exhibit both cytoplasmic and nuclear changes characteristic of cells undergoing apoptosis. The tTG-transfected cells express high Bcl-2 protein levels as well as phenotypic neural cell adhesion molecule markers (NCAM and neurofilaments) of cells differentiating along the neuronal pathway. In keeping with these findings, transfection of neuroblastoma cells with an expression vector containing segments of the human tTG cDNA in antisense orientation resulted in a pronounced decrease of both spontaneous and retinoic acid (RA)-induced apoptosis. We also present evidence that (i) the apoptotic program of these neuroectodermal cells is strictly regulated by RA and (ii) cell death by apoptosis in the human neuroblastoma SK-N-BE(2) cells preferentially occurs in the substrate-adherent phenotype. For the first time, we report here a direct effect of tTG in the phenotypic maturation toward apoptosis. These results indicate that the tTG-dependent irreversible cross-linking of intracellular protein represents an important biochemical event in the induction of the structural changes featuring cells dying by apoptosis.

Estradiol protects against β-amyloid (25–35)-induced toxicity in SK-N-SH human neuroblastoma cells

1996 ◽  
Vol 218 (3) ◽  
pp. 165-168 ◽  
Author(s):  
Pattie S. Green ◽  
Kelly E. Gridley ◽  
James W. Simpkins
Keyword(s):  
Neuroblastoma Cells ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
Β Amyloid

Activated α2Macroglobulin Increases β-Amyloid (25–35)-Induced Toxicity in LAN5 Human Neuroblastoma Cells

1999 ◽  
Vol 155 (2) ◽  
pp. 252-259 ◽  
Author(s):  
C. Fabrizi ◽  
R. Businaro ◽  
G.M. Lauro ◽  
G. Starace ◽  
L. Fumagalli
Keyword(s):  
Neuroblastoma Cells ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
Β Amyloid

scholarly journals Nothing Regular about the Regulins: Distinct Functional Properties of SERCA Transmembrane Peptide Regulatory Subunits

2021 ◽  
Vol 22 (16) ◽  
pp. 8891
Author(s):  
Nishadh Rathod ◽  
Jessi J. Bak ◽  
Joseph O. Primeau ◽  
M’Lynn E. Fisher ◽  
Lennane Michel Espinoza-Fonseca ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Functional Properties ◽  
Transmembrane Helices ◽  
Regulatory Subunits ◽  
Reading Frame ◽  
Endoplasmic Reticulum Calcium ◽  
Cellular Processes ◽  
Functional Consequences ◽  
Differential Binding ◽  
Dynamics Simulations

The sarco-endoplasmic reticulum calcium ATPase (SERCA) is responsible for maintaining calcium homeostasis in all eukaryotic cells by actively transporting calcium from the cytosol into the sarco-endoplasmic reticulum (SR/ER) lumen. Calcium is an important signaling ion, and the activity of SERCA is critical for a variety of cellular processes such as muscle contraction, neuronal activity, and energy metabolism. SERCA is regulated by several small transmembrane peptide subunits that are collectively known as the “regulins”. Phospholamban (PLN) and sarcolipin (SLN) are the original and most extensively studied members of the regulin family. PLN and SLN inhibit the calcium transport properties of SERCA and they are required for the proper functioning of cardiac and skeletal muscles, respectively. Myoregulin (MLN), dwarf open reading frame (DWORF), endoregulin (ELN), and another-regulin (ALN) are newly discovered tissue-specific regulators of SERCA. Herein, we compare the functional properties of the regulin family of SERCA transmembrane peptide subunits and consider their regulatory mechanisms in the context of the physiological and pathophysiological roles of these peptides. We present new functional data for human MLN, ELN, and ALN, demonstrating that they are inhibitors of SERCA with distinct functional consequences. Molecular modeling and molecular dynamics simulations of SERCA in complex with the transmembrane domains of MLN and ALN provide insights into how differential binding to the so-called inhibitory groove of SERCA—formed by transmembrane helices M2, M6, and M9—can result in distinct functional outcomes.

scholarly journals The antioxidant xanthorrhizol prevents amyloid-β-induced oxidative modification and inactivation of neprilysin

2018 ◽  
Vol 38 (1) ◽  
Author(s):  
Chol Seung Lim ◽  
Jung-Soo Han
Keyword(s):  
Therapeutic Potential ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Enzymatic Activities ◽  
Oxidative Modification ◽  
Amyloid Β Peptide ◽  
Oxygen Species ◽  
Human Neuroblastoma Cells ◽  
Neuroprotective Effects ◽  
Human Neuroblastoma

Activity of neprilysin (NEP), the major protease which cleaves amyloid-β peptide (Aβ), is reportedly reduced in the brains of patients with Alzheimer’s disease (AD). Accumulation of Aβ generates reactive oxygen species (ROS) such as 4-hydroxynonenal (HNE), and then reduces activities of Aβ-degrading enzymes including NEP. Xanthorrhizol (Xan), a natural sesquiterpenoid, has been reported to possess antioxidant and anti-inflammatory properties. The present study examined the effects of Xan on HNE- or oligomeric Aβ42-induced oxidative modification of NEP protein. Xan was added to the HNE- or oligomeric Aβ42-treated SK-N-SH human neuroblastoma cells and then levels, oxidative modification and enzymatic activities of NEP protein were measured. Increased HNE levels on NEP proteins and reduced enzymatic activities of NEP were observed in the HNE- or oligomeric Aβ42-treated cells. Xan reduced HNE levels on NEP proteins and preserved enzymatic activities of NEP in HNE- or oligomeric Aβ42-treated cells. Xan reduced Aβ42 accumulation and protected neurones against oligomeric Aβ42-induced neurotoxicity through preservation of NEP activities. These findings indicate that Xan possesses therapeutic potential for the treatment of neurodegenerative diseases, including AD, and suggest a potential mechanism for the neuroprotective effects of antioxidants for the prevention of AD.

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