(649f) Amyloid-β Protein Aggregates Selectively Activate Brain Endothelium for Adhesion Via Nuclear Factor-κB-Mediated Upregulation of Cell Surface Adhesion Molecules

Cerebral amyloid angiopathy (CAA) associated with Alzheimer's disease (AD) is characterized by the presence of amyloid plaques in the brain cerebrovasculature. These deposits are comprised primarily of the fibrillar form of the amyloid-β protein (Aβ), generated via self-association of Aβ monomer. Vascular accumulation of fibrillar Aβ occurs primarily in the basement membrane and initiates a cascade of events culminating in a weakening of the vessel wall that may lead to stroke as a result of cerebral hemorrhage. Among these events is an increase in the adhesion of circulating monocyte cells, which is suggested to contribute to the elevated neuroinflammation observed in AD brain.

We have employed human brain microvasculature endothelial cells (HBMVECs) to assess the ability of aggregated Aβ to stimulate endothelial monolayers for adhesion of monocyte cells. Isolated soluble Aβ aggregates, which are intermediates along the Aβ self-assembly pathway between unaggregated monomer and mature fibril, selectively activated endothothelial monolayers for both adhesion and subsequent transmigration of monocyte cells. In contrast, unaggregated Aβ monomer and mature Aβ fibril failed to induce any change in endothelial adhesion. Correlations between average Aβ aggregate size and observed increases in endothelial adhesion illustrated that smaller soluble aggregates are more potent activators of endothelium.

The upregulation of endothelial cell surface adhesion molecules ICAM-1 and VCAM-1 was also selectively induced by isolated soluble Aβ aggregation intermediates. Furthermore, blockage of endothelial ICAM-1 and VCAM-1 abrogated Aβ-stimulated adhesion of monocyte cells, confirming a role for these adhesion molecules in the stimulation of endothelial adhesion by Aβ aggregates. In parallel, isolated soluble Aβ aggregation intermediates induced nuclear translocation of the nuclear factor-κB (NF-κB) transcription factor. The direct involvement of NF-κB in the stimulation of endothelial adhesion by Aβ aggregates was demonstrated by the blockage of NF-κB nuclear translocation using an inhibitor which halts the proteolytic degradation machinery that exposes the nuclear translocation signal within the protein. This inhibitor prevented both Aβ-stimulated adhesion molecule expression and subsequent increases in monocyte adhesion.

Together, these results demonstrate that small soluble aggregates of the Aβ protein can selectively activate brain microvascular endothelium for the adhesion of circulating monocytes via NF-κB-mediated upregulation of VCAM-1 and ICAM-1. Elucidation of this pathway identifies potential novel targets for therapeutic intervention which could decrease AD-associated chronic inflammation that can contribute to disease pathogenesis.