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

Cerebrovascular accumulation of amyloid-beta protein (A beta) aggregates in Alzheimer's disease (AD) is proposed to contribute to disease progression and brain inflammation as a result of A beta-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-kappa B (NF-kappa B) in the activation of cerebral microvascular endothelial cells by A beta is explored. Quantitative immunocytochemistry is employed to demonstrate that A beta(1-40) preparations containing isolated soluble aggregates elicit the most pronounced activation and nuclear translocation of NF-kappa B. This rapid and transient response is observed down to physiological A beta concentrations and parallels phenotypic changes in endothelial monolayers that are selectively elicited by soluble A beta(1-40) aggregates. While monomeric and fibrillar preparations of A beta(1-40) also activated NF-kappa B, this response was less pronounced, limited to a small cell population, and not coupled with phenotypic changes. Soluble A beta(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-kappa B activation. Together, these results provide additional evidence indicating a role for soluble A beta aggregates in the activation of the cerebral microvascular endothelium and implicate the involvement of NF-kappa B signaling pathways in A beta stimulation of endothelial dysfunction associated with AD.