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J Neurosci. 2012 Jun 27;32(26):8845-54. doi: 10.1523/JNEUROSCI.6102-11.2012.

Aβ₁₋₄₂-RAGE interaction disrupts tight junctions of the blood-brain barrier via Ca²⁺-calcineurin signaling.

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  • 1Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul 110-799, Korea.


The blood-brain barrier (BBB), which is formed by adherens and tight junctions (TJs) of endothelial cells, maintains homeostasis of the brain. Disrupted intracellular Ca²⁺ 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 β-peptide (Aβ) and mediate Aβ transport across the BBB, contributing to the deposition of Aβ in the brain. However, molecular mechanisms underlying Aβ-RAGE interaction-induced alterations in the BBB have not been identified. We found that Aβ₁₋₄₂ 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 Aβ₁₋₄₂-induced changes in ZO-1, suggesting that Aβ-RAGE interactions alter TJ proteins through the Ca²⁺-calcineurin pathway. Consistent with these in vitro findings, we found disrupted microvessels near Aβ 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 Aβ-RAGE interaction-induced breakage of BBB integrity. This pathway might play an important role in the pathogenesis of AD.

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