Abstract
Amyloid-β peptides (Aβ) exist in several forms and are known as key modulators of Alzheimer’s disease (AD). Fibrillary Aβ (fAβ) has been found to disrupt the blood-brain barrier (BBB) by triggering and promoting inflammation. In this study, luteolin, a naturally occurring flavonoid that has shown beneficial properties in the central nervous system, was evaluated as a potential agent to preserve barrier function and inhibit inflammatory responses at the BBB that was injured by fAβ1–40. We established an in vitro BBB model by co-culturing human brain microvascular endothelial cells (hBMECs) and human astrocytes (hAs) under fAβ1–40-damaged conditions and investigated the effect of luteolin by analyzing cellular toxicity, barrier function, cytokine production and inflammation-related intracellular signaling pathways. Our results demonstrated that, in cells injured by fAβ1–40, luteolin increased cell viability of hBMECs and hAs. The cytoprotection of the co-culture against the damage induced by fAβ1–40 was also increased at both the apical and basolateral sides. Luteolin protected the barrier function by preserving transendothelial electrical resistance and relieving aggravated permeability in the human BBB model after being exposed to fAβ1–40. Moreover, in both the apical and basolateral sides of the co-culture, luteolin reduced fAβ1–40-induced inflammatory mediator and cytokine production, including cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1 β (IL-1β), interleukin 6 (IL-6), and interleukin 8 (IL-8), however it did not show sufficient effects on scavenging intracellular reactive oxygen species (ROS) in hBMECs and hAs. The mechanism of BBB protection against fAβ1–40-induced injury may be related to the regulation of inflammatory signal transduction, which involves inhibition of p38 mitogen-activated protein kinase (MAPK) activation, downregulation of phosphorylated inhibitory κB kinase (phosphor-IKK) levels, relief of inhibitory κB α (IκBα) degradation, blockage of nuclear factor κB (NF-κB) p65 nuclear translocation, and reduction of the release of inflammatory cytokines. Moreover, the employment of p38 MAPK and NF-κB inhibitors reversed luteolin-mediated barrier function and cytokine release. Taken together, luteolin may serve as a potential therapeutic agent for BBB protection by inhibiting inflammation following fAβ1–40-induced injury.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and has a high morbidity and mortality [1]
The results showed that luteolin increased cell cell viability of human brain microvascular endothelial cells (hBMECs) and human astrocytes (hAs) that were injured by fibrillar Aβ 1–40 (fAβ1–40) treatment
We further found that nuclear factor κB (NF-κB) inhibition by the inhibitor pyrrolidine dithiocarbamate (PDTC) reversed the effects of luteolin on fAβ1–40 -induced blood-brain barrier (BBB) dysfunction and cytokine release
Summary
Alzheimer’s disease (AD) is the most common form of dementia and has a high morbidity and mortality [1]. It is well documented that fibrillary forms of Aβ may serve as an inflammatory stimulus for neuroinflammatory responses and the underlying mechanisms have been explored in a variety of studies [3,4,5,6]. Increasing evidence suggests that components of the blood-brain barrier (BBB) can be highly responsive to inflammation caused by different forms of Aβ [7,8,9], which could either potentially contribute to events leading to subsequent neurodegeneration, or act as inflammatory mediators to potentiate the deleterious neuroinflammatory cycle. A better understanding of the processes and mechanisms that result in Aβ-related inflammation of the BBB may lead to novel therapeutics to combat AD
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