Abstract
Cerebrovascular accumulation of amyloid-β protein (Aβ) aggregates in Alzheimers disease (AD) is proposed to contribute to disease progression and brain inflammation as a result of Aβ-induced increases in endothelial monolayer permeability and stimulation of the endothelium for cellular adhesion and transmigration. These deficiencies facilitate the entry of serum proteins and monocyte-derived microglia into the brain. In the current study, a role for nuclear factor-κB (NF-κB) in the activation of cerebral microvascular endothelial cells by Aβ is explored. Quantitative immunocytochemistry is employed to demonstrate that Aβ1-40 preparations containing isolated soluble aggregates elicit the most pronounced activation and nuclear translocation of NF-κB. This rapid and transient response is observed down to physiological Aβ concentrations and parallels phenotypic changes in endothelial monolayers that are selectively elicited by soluble Aβ1-40 aggregates. While monomeric and fibrillar preparations of Aβ1-40 also activated NF-κB, this response was less pronounced, limited to a small cell population, and not coupled with phenotypic changes. Soluble Aβ1-40 aggregate stimulation of endothelial monolayers for adhesion and subsequent transmigration of monocytes as well as increases in permeability were abrogated by inhibition of NF-κB activation. Together, these results provide additional evidence indicating a role for soluble Aβ aggregates in the activation of the cerebral microvascular endothelium and implicate the involvement of NF-κB signaling pathways in Aβ stimulation of endothelial dysfunction associated with AD.
Keywords: Alzheimer's disease, amyloid-β protein, cerebral amyloid angiopathy, nuclear factor-κB, blood-brain barrier, soluble aggregates, cerebral microvasculature, endothelium, immunocytochemistry, c3b, transendothelial migration, permeability, monocytes, optical image analysis
Current Alzheimer Research
Title: Activation of Brain Endothelium by Soluble Aggregates of the Amyloid-β Protein Involves Nuclear Factor-κB
Volume: 8 Issue: 1
Author(s): Francisco J. Gonzalez-Velasquez, J. Will Reed, John W. Fuseler, Emily E. Matherly, Joseph A. Kotarek, Deborah D. Soto-Ortega and Melissa A. Moss
Affiliation:
Keywords: Alzheimer's disease, amyloid-β protein, cerebral amyloid angiopathy, nuclear factor-κB, blood-brain barrier, soluble aggregates, cerebral microvasculature, endothelium, immunocytochemistry, c3b, transendothelial migration, permeability, monocytes, optical image analysis
Abstract: Cerebrovascular accumulation of amyloid-β protein (Aβ) aggregates in Alzheimers disease (AD) is proposed to contribute to disease progression and brain inflammation as a result of Aβ-induced increases in endothelial monolayer permeability and stimulation of the endothelium for cellular adhesion and transmigration. These deficiencies facilitate the entry of serum proteins and monocyte-derived microglia into the brain. In the current study, a role for nuclear factor-κB (NF-κB) in the activation of cerebral microvascular endothelial cells by Aβ is explored. Quantitative immunocytochemistry is employed to demonstrate that Aβ1-40 preparations containing isolated soluble aggregates elicit the most pronounced activation and nuclear translocation of NF-κB. This rapid and transient response is observed down to physiological Aβ concentrations and parallels phenotypic changes in endothelial monolayers that are selectively elicited by soluble Aβ1-40 aggregates. While monomeric and fibrillar preparations of Aβ1-40 also activated NF-κB, this response was less pronounced, limited to a small cell population, and not coupled with phenotypic changes. Soluble Aβ1-40 aggregate stimulation of endothelial monolayers for adhesion and subsequent transmigration of monocytes as well as increases in permeability were abrogated by inhibition of NF-κB activation. Together, these results provide additional evidence indicating a role for soluble Aβ aggregates in the activation of the cerebral microvascular endothelium and implicate the involvement of NF-κB signaling pathways in Aβ stimulation of endothelial dysfunction associated with AD.
Export Options
About this article
Cite this article as:
J. Gonzalez-Velasquez Francisco, Will Reed J., W. Fuseler John, E. Matherly Emily, A. Kotarek Joseph, D. Soto-Ortega Deborah and A. Moss Melissa, Activation of Brain Endothelium by Soluble Aggregates of the Amyloid-β Protein Involves Nuclear Factor-κB, Current Alzheimer Research 2011; 8 (1) . https://dx.doi.org/10.2174/156720511794604606
DOI https://dx.doi.org/10.2174/156720511794604606 |
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
-
Taking Cell Culture in Drug Discovery to the Third Dimension - A Patent Review
Recent Patents on Biomedical Engineering (Discontinued) Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors
Current Medicinal Chemistry Leptin and Interleukin-1β Modulate Neuronal Glutamate Release and Protect Against Glucose-Oxygen-Serum Deprivation
Current Neurovascular Research Quantitative Proteomics in the Study of Phosphotyrosine-Mediated Signal Transduction Pathway
Current Proteomics Dynamic Expression of MicroRNAs (183, 135a, 125b, 128, 30c and 27a) in the Rat Pilocarpine Model and Temporal Lobe Epilepsy Patients
CNS & Neurological Disorders - Drug Targets Voltage Gated ion Channels: Targets for Anticonvulsant Drugs
Current Topics in Medicinal Chemistry Exploiting Internal Ribosome Entry Sites in Gene Therapy Vector Design
Current Gene Therapy Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease
Current Medicinal Chemistry Relevance of the Neuropeptide Y System in the Biology of Cancer Progression
Current Topics in Medicinal Chemistry Na<sup>+</sup>/K<sup>+</sup> ATPase Inhibitors in Cancer
Current Drug Targets Indoleamine 2,3-Dioxygenase in Immune Suppression and Cancer
Current Cancer Drug Targets The Role of Iron Toxicity in Oxidative Stress-induced Cellular Degeneration in Down Syndrome: Protective Effects of Phenolic Antioxidants
Current Nutrition & Food Science Pharmacokinetic and Pharmacogenetic Predictive Markers of Irinotecan Activity and Toxicity
Current Drug Metabolism Ferulic Acid and Alzheimer’s Disease: Promises and Pitfalls
Mini-Reviews in Medicinal Chemistry Thiosemicarbazones as Potent Anticancer Agents and their Modes of Action
Mini-Reviews in Medicinal Chemistry The role of Nox-mediated oxidation in the regulation of cytoskeletal dynamics
Current Pharmaceutical Design Applications of High Content Screening in Life Science Research
Combinatorial Chemistry & High Throughput Screening Amino Acid Degrading Enzymes and their Application in Cancer Therapy
Current Medicinal Chemistry Developments in the Application of 1,2,3-Triazoles in Cancer Treatment
Recent Patents on Anti-Cancer Drug Discovery Neuroprotective Properties of Peroxisome Proliferator-Activated Receptor Alpha (PPARα) and its Lipid Ligands
Current Medicinal Chemistry