While Alzheimer's disease (AD) represents the leading cause of dementia in the elderly, FDA-approved therapeutics remain inadequate, leading patients to explore complimentary and alternative medicine approaches. Copious epidemiological evidence suggests that plant-derived polyphenols prevent or attenuate AD. These observations are not unexpected as many polyphenols can both inhibit the assembly of aggregated forms of the amyloid-Beta protein, which are associated with disease pathology, and act as antioxidants to counter inflammation, a ubiquitous feature of AD brain. Insight into the mechanism by which polyphenols intervene within AD pathogenesis will allow for the directed design of complimentary medicine approaches. Specifically, cerebrovascular inflammation, an early event in the pathogenesis of AD, represents a potential target for polyphenols. Our laboratory has demonstrated that soluble ABeta aggregates selectively stimulate brain endothelial monolayers for NF-kB mediated inflammatory responses, including elevated monolayer permeability and an increased ability to bind monocytes. Our findings demonstrate that ABeta-induced vascular inflammation presents two prospective targets for polyphenol intervention: (1) preventing the formation of soluble ABeta aggregates from monomeric protein and (2) blocking NF-kB signaling pathways by neutralizing reactive oxygen species (ROS) second messengers. Accordingly, the proposed research will consider the hypothesis that polyphenols can reduce ABeta-induced inflammatory responses in cerebrovascular endothelial cells by interfering with both ABeta aggregation and ROS second messengers. This hypothesis will be initially tested using a group of structurally similar polyphenols that our laboratory has evaluated for inhibition in mechanistic-specific aggregation assays to illustrate variations in their anti-aggregation capabilities.
In Aim 1, the hypothesis that inhibition of ABeta aggregation by polyphenols decreases ABeta-induced vascular inflammatory responses will be examined by comparing brain endothelial monolayers treated with ABeta aggregates prepared in the presence of polyphenols capable or incapable of inhibiting ABeta aggregation. NF-kB activation will be used as an initial measure of endothelial perturbation and followed by monolayer permeability and monocyte adhesion assays to substantiate effects upon inflammation. Subsequent experiments will incorporate mechanistic-specific ABeta aggregation assays to extend investigation to additional polyphenols with diverse structures.
In Aim 2. the hypothesis that inhibition of ROS second messengers by polyphenols decreases ABeta-induced vascular inflammatory responses will be explored by comparing polyphenol antioxidant capacity with the attenuation of endothelial NF-kB activation and associated inflammatory responses induced by pre-formed ABeta aggregates. Substantiation of the dual action of polyphenols in mitigation of vascular inflammation will direct polyphenol-based complimentary medicine approaches toward polyphenols with both anti-aggregation and antioxidant capabilities.
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