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.
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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 |
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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
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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
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