Soluble Amyloid-beta Protein Aggregates Induce Nuclear Factor-kappa B Mediated Upregulation of Adhesion Molecule Expression to Stimulate Brain Endothelium for Monocyte Adhesion

The adhesion of circulating monocytes to cerebrovascular endothelium has the potential to contribute to the pathogenesis of Alzheimer's disease (AD). In AD, the amyloid-beta protein (A beta) assembles to form fibrils that deposit within both the brain parenchyma and the cerebrovasculature. Soluble A beta aggregates, intermediates on the pathway to mature fibril formation, are responsible for the stimulation of brain microvascular endothelial cells for increased adhesion of monocytes. However, a related role for soluble A beta aggregates in the upregulation of endothelial cell surface adhesion molecules that support monocyte adhesion remains to be demonstrated. The current study establishes that upregulation of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on the surface of human brain microvascular endothelial cells is selectively induced by soluble A beta(1-40) aggregates, while unaggregated monomer and mature fibril fail to elicit a substantial increase in adhesion molecule expression. A beta induced changes in VCAM-1 and ICAM-1 expression are transient and are mediated by NF-kappa B activation. Both VCAM-1 and ICAM-1 participate in A beta(1-40) aggregate stimulated endothelial-monocyte adhesion. VCAM-1 plays an essential role in this cell adhesion event, while ICAM-1 presents a less pronounced contribution. These results delineate a selective role for soluble A beta aggregates in the stimulation of brain endothelium via the NF-kappa B mediated upregulation of cell surface adhesion molecules VCAM-1 and ICAM-1 to augment monocyte adhesion, the first step for infiltration of monocytes across the blood-brain barrier where they can exacerbate AD pathogenesis. (C) Koninklijke Brill NV, Leiden, 2010