Activation of Brain Endothelium by Soluble Aggregates of the Amyloid-β Protein Involves Nuclear Factor-κB

Author(s): Francisco J. Gonzalez-Velasquez, J. Will Reed, John W. Fuseler, Emily E. Matherly, Joseph A. Kotarek, Deborah D. Soto-Ortega, Melissa A. Moss.

Journal Name: Current Alzheimer Research

Volume 8 , Issue 1 , 2011

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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

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Article Details

VOLUME: 8
ISSUE: 1
Year: 2011
Page: [81 - 94]
Pages: 14
DOI: 10.2174/156720511794604606

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