Abstract
Several lines of evidence suggest that the initial events of amyloid-β peptide (Aβ) oligomerization and deposition in Alzheimer’s disease (AD) involve the interaction of soluble oligomers with neuronal membranes. In this study, we show that Aβ42 oligomers are recruited to lipid rafts, which are ordered membrane microdomains rich in cholesterol and gangliosides, resulting in lipid peroxidation, Ca2+ dyshomeostasis and membrane permeabilization in primary fibroblasts from familial AD patients (FAD) bearing APPVal717Ile, PS-1Leu392Val or PS-1Met146Leu gene mutations. Moreover, the presence of significantly higher levels of lipid peroxidation correlated with greater structural modification in detergent resistant domains (DRMs) isolated from APP and PS-1 fibroblasts, compared to WT fibroblasts from healthy subjects. Modulation of raft GM1, including modest depletion of GM1 content and interference with GM1 exposure or negative charge, precluded the interaction of amyloid aggregates with the plasma membrane and the resulting cell damage in FAD fibroblasts and rat brains cortical neurons. These findings suggest a specific role for raft domains as primary mediators of amyloid toxicity in AD neurons.
Keywords: Alzheimer’s disease fibroblasts, amyloid aggregate toxicity, calcium dysregulation, membrane GM1, oxidative stress, primary cortical neurons
Current Alzheimer Research
Title:Lipid Rafts Mediate Amyloid-Induced Calcium Dyshomeostasis and Oxidative Stress in Alzheimer’s Disease
Volume: 10 Issue: 2
Author(s): Elisa Evangelisti, Daniel Wright, Mariagioia Zampagni, Roberta Cascella, Claudia Fiorillo, Silvia Bagnoli, Annalisa Relini, Daniela Nichino, Tania Scartabelli, Benedetta Nacmias, Sandro Sorbi and Cristina Cecchi
Affiliation:
Keywords: Alzheimer’s disease fibroblasts, amyloid aggregate toxicity, calcium dysregulation, membrane GM1, oxidative stress, primary cortical neurons
Abstract: Several lines of evidence suggest that the initial events of amyloid-β peptide (Aβ) oligomerization and deposition in Alzheimer’s disease (AD) involve the interaction of soluble oligomers with neuronal membranes. In this study, we show that Aβ42 oligomers are recruited to lipid rafts, which are ordered membrane microdomains rich in cholesterol and gangliosides, resulting in lipid peroxidation, Ca2+ dyshomeostasis and membrane permeabilization in primary fibroblasts from familial AD patients (FAD) bearing APPVal717Ile, PS-1Leu392Val or PS-1Met146Leu gene mutations. Moreover, the presence of significantly higher levels of lipid peroxidation correlated with greater structural modification in detergent resistant domains (DRMs) isolated from APP and PS-1 fibroblasts, compared to WT fibroblasts from healthy subjects. Modulation of raft GM1, including modest depletion of GM1 content and interference with GM1 exposure or negative charge, precluded the interaction of amyloid aggregates with the plasma membrane and the resulting cell damage in FAD fibroblasts and rat brains cortical neurons. These findings suggest a specific role for raft domains as primary mediators of amyloid toxicity in AD neurons.
Export Options
About this article
Cite this article as:
Evangelisti Elisa, Wright Daniel, Zampagni Mariagioia, Cascella Roberta, Fiorillo Claudia, Bagnoli Silvia, Relini Annalisa, Nichino Daniela, Scartabelli Tania, Nacmias Benedetta, Sorbi Sandro and Cecchi Cristina, Lipid Rafts Mediate Amyloid-Induced Calcium Dyshomeostasis and Oxidative Stress in Alzheimer’s Disease, Current Alzheimer Research 2013; 10 (2) . https://dx.doi.org/10.2174/1567205011310020004
DOI https://dx.doi.org/10.2174/1567205011310020004 |
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
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
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...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
-
Melatonin, its Metabolites and its Synthetic Analogs as Multi-Faceted Compounds: Antioxidant, Prooxidant and Inhibitor of Bioactivation Reactions
Current Medicinal Chemistry Cannabinoids and Neuro-Inflammation: Regulation of Brain Immune Response
Recent Patents on CNS Drug Discovery (Discontinued) Nampt/Visfatin/PBEF: A Functionally Multi-faceted Protein with a Pivotal Role in Malignant Tumors
Current Pharmaceutical Design Differential Effects of Doxazosin on Renin-Angiotensin-System- Regulating Aminopeptidase Activities in Neuroblastoma and Glioma Tumoral Cells
CNS & Neurological Disorders - Drug Targets Viral Induced Oxidative and Inflammatory Response in Alzheimer’s Disease Pathogenesis with Identification of Potential Drug Candidates: A Systematic Review using Systems Biology Approach
Current Neuropharmacology Collective Roles of Molecular Chaperones in Protein Degradation Pathways Associated with Neurodegenerative Diseases
Current Pharmaceutical Biotechnology The Identification and Characterization of Excitotoxic Nerve-endings in Alzheimer Disease
Current Alzheimer Research The Effect of Different microRNA Backbones on Artificial miRNA Expression and Knockdown Activity Against HIV-1 Replication
MicroRNA Dynamic Crosstalk between GlcNAcylation and Phosphorylation: Roles in Signaling, Transcription and Human Disease
Current Signal Transduction Therapy Inhibitors of the TGF-β Superfamily and their Clinical Applications
Mini-Reviews in Medicinal Chemistry Basic Mechanisms Involved in the Anti-Cancer Effects of Melatonin
Current Medicinal Chemistry Synthetic 2-Methoxyestradiol Derivatives: Structure-Activity Relationships
Current Medicinal Chemistry Peptide-Drug Conjugate: A Novel Drug Design Approach
Current Medicinal Chemistry The Impact of Proteomics in the Understanding of the Molecular Basis of Paclitaxel-Resistance in Ovarian Tumors
Current Cancer Drug Targets Vaccine Ingredients: Components that Influence Vaccine Efficacy
Mini-Reviews in Medicinal Chemistry Selective Inhibitors of Histone Deacetylase 10 (HDAC-10)
Current Medicinal Chemistry The Role of β-Amyloid Protein in Synaptic Function: Implications for Alzheimers Disease Therapy
Current Neuropharmacology Therapeutic Peptide Mimetics Looking for a Turn to Block Aberrant Players of Malignancy
Current Cancer Therapy Reviews Vascular Targeting: A New Antitumor Activity
Drug Design Reviews - Online (Discontinued) The Neurotachykinin NK1 Receptor – A Novel Target for Diagnostics and Therapy
Current Molecular Imaging (Discontinued)