Alzheimer's disease (AD), the leading cause of dementia in the elderly, is characterized by the presence of amyloid plaques in the brain parenchyma and cerebrovasculature. These deposits are comprised primarily of the fibrillar form of the amyloid-beta protein. Monomeric amyloid-beta self-associates to form the fibrillar amyloid-beta that deposits as amyloid plaques. Vascular accumulation of fibrillar amyloid-beta 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. Amyloid-beta has been shown to elicit a number of responses in endothelial cells that contribute to these events; however, the mechanism for this stimulation remains unknown.

We have employed human brain microvasculature endothelial cell (HBMVEC) monolayers to assess the physiological effect of various amyloid-beta preparations. Amyloid-beta(1-40) monomer, fibril, and soluble aggregates were prepared and isolated using a combination of size exclusion chromatography (SEC) and centrifugation, and aggregate size was characterized using dynamic light scattering (DLS). Experimental data demonstrates that isolated soluble amyloid-beta(1-40) aggregation intermediates selectively activate endothothelial monolayers for both adhesion and subsequent transmigration of monocyte cells, as well as increased permeability, in the absence of endothelial cell death. In contrast, unaggregated amyloid-beta(1-40) monomer and mature amyloid-beta(1-40) fibril fail to induce any change in endothelial adhesion, transmigration, or permeability. Correlations between average amyloid-beta aggregate size and observed increases in both adhesion and monolayer permeability illustrate that smaller soluble aggregates are more potent activators of endothelium. Immunocytochemistry further reveals that NF-kappaB signaling cascades are involved in amyloid-beta stimulation of endothelium. These results support previous studies demonstrating heightened neuronal activity of soluble amyloid-beta aggregates, and further show that soluble aggregates also selectively exhibit activity in a vascular cell model.

As the contribution of vascular amyloid deposition in the progression of AD continues to gain support, therapeutic strategies should begin to encompass this vital facet of the disease. Resolution of the interactions between vascular amyloid-beta deposits and the endothelium will distinguish potential therapeutic targets for the reduction of vascular damage associated with AD.