AMYLOID-PEPTIDE ACCELERATES ALTERATIONS OF EXPRESSION AND LOCALIZATION OF TIGHT JUNCTION PROTEINS VIA RAGE

Abstract

The blood-brain barrier (BBB) is the specialized barrier formed by the endothelial cells and an important role in regulating transport of various molecules and maintaining integrity and brain homeostasis. Deposition of amyloid b-peptide (Ab) in the brain is the prominent feature of Alzheimers disease (AD). Accumulation of Ab leads to increase activated microglia and astrocytes, resulting in alteration of brain microenvironment and BBB breakdown. The brain endothelium forming the BBB is connected by tight junction proteins including ZO-1 and occludin, restricting paracellular permeability in selective. The receptor for advanced glycation end products (RAGE) binds soluble Ab and is thought to be a major transporter of Ab across BBB. Influx of Ab by RAGE from blood to brain elevates deposition of Ab in the brain including around BBB. From the point of view the overexpression of RAGE in AD brain vasculature, as well as RAGE-dependent binding and transport of Ab, we hypothesized that enhanced RAGE-mediated Ab may accelerate BBB disruption by inducing alteration of tight junction proteins and paracellular permeability. We attempt to explore tight junction proteins may be altered by Ab following up-regulation of RAGE in the immortalized mouse brain capillary endothelial cell line, bEnd3 cells, as an in vitro BBB model. We observed that Ab altered the expression of ZO-1 and occludin mRNA and protein as well as the localization of those proteins in vitro. It indicates that Ab causes the alteration of mRNA, protein and localization of tight junction proteins and it is accelerated in RAGE-overexpressing bEnd3 cells, suggesting that RAGE-Ab interaction might be important for change of the BBB integrity in AD patients.