Aß1₋42-RAGE interaction disrupts tight junctions of the blood-brain barrier via Ca²âº-calcineurin signaling.

The blood-brain barrier (BBB), which is formed by adherens and tight junctions (TJs) of endothelial cells, maintains homeostasis of the brain. Disrupted intracellular Ca²âº homeostasis and breakdown of the BBB have been implicated in the pathogenesis of Alzheimer's disease (AD). The receptor for advanced glycation end products (RAGE) is known to interact with amyloid ß-peptide (Aß) and mediate Aß transport across the BBB, contributing to the deposition of Aß in the brain. However, molecular mechanisms underlying Aß-RAGE interaction-induced alterations in the BBB have not been identified. We found that Aß1₋42 induces enhanced permeability, disruption of zonula occludin-1 (ZO-1) expression in the plasma membrane, and increased intracellular calcium and matrix metalloproteinase (MMP) secretion in cultured endothelial cells. Neutralizing antibodies against RAGE and inhibitors of calcineurin and MMPs prevented Aß1₋42-induced changes in ZO-1, suggesting that Aß-RAGE interactions alter TJ proteins through the Ca²âº-calcineurin pathway. Consistent with these in vitro findings, we found disrupted microvessels near Aß plaque-deposited areas, elevated RAGE expression, and enhanced MMP secretion in microvessels of the brains of 5XFAD mice, an animal model for AD. We have identified a potential molecular pathway underlying Aß-RAGE interaction-induced breakage of BBB integrity. This pathway might play an important role in the pathogenesis of AD.