Abstract
Alzheimers disease (AD) is characterized by the aggregation and subsequent deposition of misfolded β- amyloid (Aβ) peptide. The unfolded protein response (UPR) is activated by misfolded protein stress in the endoplasmic reticulum (ER). In previous studies we demonstrated mild activation of the UPR by extracellularly applied oligomeric but not fibrillar Aβ1-42. In addition, we showed that oligomeric Aβ1-42 is internalized by cells, whereas fibrillar Aβ1-42 remains on the outside of the cell. Inhibition of Aβ uptake specifically inhibits toxicity of Aβ1-42 oligomers, underscoring the toxic potential of intracellular Aβ. Therefore, in the present study, we investigated the connection between intracellularly produced Aβ and the ER stress response, using human neuroblastoma cells overexpressing either wild type APP695 (APPwt) or APP695V717F (APPmut). Both cell lines secrete higher levels of Aβ1-40 and Aβ1-42 compared to the parental line. In addition, APPmut produces more Aβ1-42 than APPwt. Whereas the basal levels of UPR markers are not different, we find augmented UPR induction in response to ER stress in both APP overproducing cell lines compared to the parental cell line, with the strongest UPR activation in APPmut cells. In addition, ER stress toxicity was highest in APPmut cells, strongly suggesting a connection with the production of Aβ1-42. The difference in ER stress mediated toxicity between the APPwt and APPmut cell lines is alleviated by pretreatment with γ-secretase inhibitor, indicating that it is dependent on Aβ production and in particular on Aβ1-42. Our data indicate that increased Aβ1-42 production sensitizes neuroblastoma cells for ER stress toxicity.
Keywords: Alzheimer's disease, β-Amyloid, intracellular, endoplasmic reticulum, unfolded protein response
Current Alzheimer Research
Title: Increased Aβ1-42 Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity
Volume: 5 Issue: 5
Author(s): Sidhartha M. Chafekar, Rob Zwart, Robert Veerhuis, H. Vanderstichele, Frank Baas and Wiep Scheper
Affiliation:
Keywords: Alzheimer's disease, β-Amyloid, intracellular, endoplasmic reticulum, unfolded protein response
Abstract: Alzheimers disease (AD) is characterized by the aggregation and subsequent deposition of misfolded β- amyloid (Aβ) peptide. The unfolded protein response (UPR) is activated by misfolded protein stress in the endoplasmic reticulum (ER). In previous studies we demonstrated mild activation of the UPR by extracellularly applied oligomeric but not fibrillar Aβ1-42. In addition, we showed that oligomeric Aβ1-42 is internalized by cells, whereas fibrillar Aβ1-42 remains on the outside of the cell. Inhibition of Aβ uptake specifically inhibits toxicity of Aβ1-42 oligomers, underscoring the toxic potential of intracellular Aβ. Therefore, in the present study, we investigated the connection between intracellularly produced Aβ and the ER stress response, using human neuroblastoma cells overexpressing either wild type APP695 (APPwt) or APP695V717F (APPmut). Both cell lines secrete higher levels of Aβ1-40 and Aβ1-42 compared to the parental line. In addition, APPmut produces more Aβ1-42 than APPwt. Whereas the basal levels of UPR markers are not different, we find augmented UPR induction in response to ER stress in both APP overproducing cell lines compared to the parental cell line, with the strongest UPR activation in APPmut cells. In addition, ER stress toxicity was highest in APPmut cells, strongly suggesting a connection with the production of Aβ1-42. The difference in ER stress mediated toxicity between the APPwt and APPmut cell lines is alleviated by pretreatment with γ-secretase inhibitor, indicating that it is dependent on Aβ production and in particular on Aβ1-42. Our data indicate that increased Aβ1-42 production sensitizes neuroblastoma cells for ER stress toxicity.
Export Options
About this article
Cite this article as:
Chafekar M. Sidhartha, Zwart Rob, Veerhuis Robert, Vanderstichele H., Baas Frank and Scheper Wiep, Increased Aβ1-42 Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity, Current Alzheimer Research 2008; 5 (5) . https://dx.doi.org/10.2174/156720508785908883
DOI https://dx.doi.org/10.2174/156720508785908883 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Alzheimer's Disease Drug Development
Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no cure or disease-modifying treatment is available yet. Therefore, the need for developing effective therapies to treat Alzheimer's disease is an urgent matter. This special issue aims to provide a comprehensive overview of ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Is there a Role for Epigenetic Enhancement of Immunomodulatory Approaches to Cancer Treatment?
Current Cancer Drug Targets Preparation and in-vitro Transfection Efficiency Evaluation of Modified Cationic Liposome-polyethyleneimine-plasmid Nanocomplexes as a Novel Gene Carrier
Current Drug Delivery Multifunctional Proteins in Tumorigenesis: Aminoacyl-tRNA Synthetases and Translational Components
Current Proteomics Anti-cancer Potential of Phyto-alkaloids: A Prospective Review
Current Cancer Therapy Reviews Monitoring T Cell Responses to Cancer Immunotherapy: Can We Now Identify Biomarkers Predicting Patients Who will be Responders
Current Cancer Therapy Reviews Development and Clinical Application of Peptide-Based Radiopharmaceuticals
Current Pharmaceutical Design Valproic Acid in the Complex Therapy of Malignant Tumors
Current Drug Targets NAD Biosynthesis in Humans - Enzymes, Metabolites and Therapeutic Aspects
Current Topics in Medicinal Chemistry Characterization of Molecular and Functional Alterations of Tumor Endothelial Cells to Design Anti-Angiogenic Strategies
Current Vascular Pharmacology Therapeutic Challenges in Neuroendocrine Tumors
Anti-Cancer Agents in Medicinal Chemistry Jatrorrhizine Protects Against Okadaic Acid Induced Oxidative Toxicity Through Inhibiting the Mitogen-Activated Protein Kinases Pathways in HT22 Hippocampal Neurons
CNS & Neurological Disorders - Drug Targets Oxidative and Nitrosative Stress and Immune-inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)
Current Neuropharmacology The Antidiabetic PPARγ Ligands: An Update on Compounds in Development
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Novel Approaches for Modulating dUTPase and Uracil-DNA Glycosylase: Potential Uses for Cancer and Viral Chemotherapy
Drug Design Reviews - Online (Discontinued) Molecular Mechanism Behind the Synergistic Activity of Diphenylmethyl Selenocyanate and Cisplatin Against Murine Tumor Model
Anti-Cancer Agents in Medicinal Chemistry Mitophagy in Carcinogenesis and Tumour Progression- A New Paradigm with Emerging Importance
Anti-Cancer Agents in Medicinal Chemistry A Medicinal Mushroom: Phellinus Linteus
Current Medicinal Chemistry Lipid Nanocarriers for Neurotherapeutics: Introduction, Challenges, Blood-brain Barrier, and Promises of Delivery Approaches
CNS & Neurological Disorders - Drug Targets Applications of Gene Transfer to Targeted Radiotherapy
Current Pharmaceutical Design Sigma-1 Receptor Chaperones and Diseases
Central Nervous System Agents in Medicinal Chemistry