title: Activation of brain endothelium by soluble aggregates of the amyloid-β protein involves nuclear factor-κB.
abstract: Cerebrovascular accumulation of amyloid-β protein (Aβ) aggregates in Alzheimer's 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 Aβ(1-40) 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 Aβ(1-40) aggregates. While monomeric and fibrillar preparations of Aβ(1-40) also activated NF-κB, this response was less pronounced, limited to a small cell population, and not coupled with phenotypic changes. Soluble Aβ(1-40) 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.
authors.affiliation: Department of Chemical Engineering, University of South Carolina, Columbia, 29208, USA.
authors.forename: Francisco  J
authors.initials: F
authors.lastname: Gonzalez-Velasquez
authors.forename: J Will
authors.initials: JW
authors.lastname: Reed
authors.forename: John W
authors.initials: JW
authors.lastname: Fuseler
authors.forename: Emily E
authors.initials: EE
authors.lastname: Matherly
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kotarek
authors.forename: Deborah D
authors.initials: DD
authors.lastname: Soto-Ortega
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Moss
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001921:Brain / Q000166:cytology*; D002448:Cell Adhesion / Q000187:drug effects; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004727:Endothelium / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007976:Leupeptins; D016328:NF-kappa B; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D006854:Hydrocortisone