Thrombin, a mediator of cerebrovascular inflammation in AD and hypoxia

Abstract

Considerable evidence implicates hypoxia and vascular inflammation in Alzheimer's disease (AD). Thrombin, a multifunctional inflammatory mediator, is demonstrable in the brains of AD patients both in the vessel walls and senile plaques. Hypoxia-inducible factor 1α (HIF-1α), a key regulator of the cellular response to hypoxia, is also upregulated in the vasculature of human AD brains. The objective of this study is to investigate inflammatory protein expression in the cerebrovasculature of transgenic AD mice and to explore the role of thrombin as a mediator of cerebrovascular inflammation and oxidative stress in AD and in hypoxia-induced changes in brain endothelial cells. Immunofluorescent analysis of the cerebrovasculature in AD mice demonstrates significant (p < 0.01–0.001) increases in thrombin, HIF-1α, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases (MMPs), and reactive oxygen species (ROS) compared to controls. Administration of the thrombin inhibitor dabigatran (100 mg/kg) to AD mice for 34 weeks significantly decreases expression of inflammatory proteins and ROS. Exposure of cultured brain endothelial cells to hypoxia for 6 h causes an upregulation of thrombin, HIF-1α, MCP-1, IL-6, and MMP2 and ROS. Treatment of endothelial cells with the dabigatran (1 nM) reduces ROS generation and inflammatory protein expression (p < 0.01–0.001). The data demonstrate that inhibition of thrombin in culture blocks the increase in inflammatory protein expression and ROS generation evoked by hypoxia. Also, administration of dabigatran to transgenic AD mice diminishes ROS levels in brain and reduces cerebrovascular expression of inflammatory proteins. Taken together, these results suggest that inhibiting thrombin generation could have therapeutic value in AD and other disorders where hypoxia, inflammation, and oxidative stress are involved.

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

“…This view is supported by the highly reactive nature of the BBB endothelium, which is both a source of, and a target for, ROS and inflammatory proteins [18,88]; and by the peculiar features of the ultrastructural damage in endothelial and perivascular cells, which is characterised by large lipid-laden vacuoles and damaged, swollen mitochondria [72]. Although a causative link between oxidative stress and microvascular damage has not been established in the AD brain in vivo, in vitro studies have shown that chronic oxidative stress increases BBB permeability, promotes leukocyte adhesion, and alters endothelial signal transduction and redox-regulated transcription factors [89].…”

“…The transcription factor HIF-1 is a key regulatory mediator of cellular responses to hypoxia, acting as sensor of low oxygen tension [18]. HIF-1 is elevated in the cerebral microcirculation of AD patients and AD mouse models [163,164], and several studies have reported elevated inflammatory proteins in brain endothelial cells exposed to hypoxia [18,164], suggesting a link between hypoxia and cerebrovascular inflammation.…”

“…Hypoperfusion-induced hypoxia evokes vascular responses, in which endothelial cells in the cerebral microcirculation play a central role. In vitro and biopsy studies have shown that hypoxia modulates endothelial junctional permeability, ROS generation [160,161] and stimulates pro-inflammatory gene expression [18,162].…”

“…BBB dysfunction mediates the indirect neurotoxic effects of chronic hypoperfusion by promoting oxidative stress [6,15,16], inflammation [17][18][19][20], impaired glucose transport across the BBB [21][22][23], BBB permeability [21,24,25], and dysregulation of nitric oxide (NO) [26][27][28], a key mediator of vascular tone and regional blood flow regulation [29,30]. As such, BBB dysfunction could mediate a vicious circle in which cerebral perfusion is reduced further and the neurodegenerative process is ac- [47,48], and by post mortem studies showing coexisting cerebrovascular disease in most AD patients [6,[49][50][51].…”

A Human-Based Integrated Framework forAlzheimer’s Disease Research

“…The presence of chronic neuroinflammation, caused by the progressive senescence of the immune system and by a sustained secretion of adipose tissue cytokines, seems to play a major role in cardiovascular disease and neurodegeneration [48], possibly contributing to AD [49,50]. The presence of high levels of both plasma and brain homocysteine (HCys) is correlated to AD and neurodegenerative disorders.…”