Current Alzheimer’s disease (AD) therapeutics remain inadequate, leading patients to explore complimentary and alternative medicine (CAM) approaches. Copious epidemiological evidence suggests that plant-derived polyphenols prevent or attenuate AD. Many plant-derived polyphenols can both inhibit the pathogenic aggregation of the amyloid-protein (A) and act as antioxidants to counter AD-associated inflammation. Specifically, cerebrovascular inflammation, an early event in AD pathogenesis, represents a potential target for polyphenols. We have demonstrated that soluble A aggregates selectively stimulate brain endothelial monolayers for NF-B mediated inflammatory responses, including elevated monolayer permeability and an increased ability to bind monocytes. Thus, A-induced vascular inflammation presents two prospective targets for polyphenol intervention: (1) preventing formation of aggregates from monomeric protein and (2) blocking NF-B signaling by neutralizing ROS second messengers. Our research considers the hypothesis that polyphenols can reduce A induced inflammatory responses in cerebrovascular endothelial cells by interfering with both A aggregation and ROS second messengers. First, we examine whether inhibition of A aggregation by polyphenols decreases A-induced vascular inflammatory responses will be examined by comparing brain endothelial monolayers treated with aggregates prepared in the presence of polyphenols capable or incapable of inhibiting A aggregation, as assessed using mechanistic-specific A aggregation assays. NF-B activation will be used as an initial measure of endothelial perturbation and followed by permeability and monocyte adhesion assays to substantiate anti-inflammatory effects. Second, we explore whether inhibition of ROS second messengers by polyphenols decreases A-induced vascular inflammatory responses will be explored by comparing polyphenol antioxidant capacity with the attenuation of NF-B activation and associated inflammatory responses induced by pre-formed aggregates. Substantiation of the dual action of polyphenols in mitigation of vascular inflammation will direct polyphenol-based CAM toward polyphenols with both anti-aggregation and antioxidant capabilities.
- F. J. Gonzalez-Velasquez, J. W. Reed, J. W. Fuseler, E. E. Matherly, J. A. Kotarek, D. D. Soto-Ortega, and M. A. Moss (2010) Activation of brain endothelium by soluble aggregates of the amyloid-b protein involves nuclear factor‑kB. Current Alzheimer’s Research, 8: 91-94.
- F. J. Gonzalez-Velasquez, J. W. Reed, J. W. Fuseler, E. E. Matherly, J. A. Kotarek, D. D. Soto-Ortega, and M. A. Moss (2010) Soluble amyloid-b protein aggregates induce nuclear factor-kB mediated upregulation of adhesion molecule expression to stimulate brain endothelium for monocyte adhesion. Journal of Adhesion Science and Technology, Invited Contribution for special issue on Adhesion and Interfacial Aspects of Cell Adhesion, 24: 2105-2129.
- F. J. Gonzalez-Velasquez, J. A. Kotarek, and M. A. Moss (2008) Soluble aggregates of the amyloid-β protein selectively stimulate permeability in human brain microvascular endothelial monolayers. Journal of Neurochemistry 107: 466-477.