Disruption of blood-brain barrier in Alzheimer disease pathogenesis

Blood-brain barrier (BBB) regulates transport of various molecules and maintains brain homeostasis. Perturbed intracellular Ca(2+) homeostasis and BBB damage have been implicated in the pathogenesis of Alzheimer disease (AD). Although receptor for advanced glycation end products (RAGE) is known to mediate Aβ transcytosis across the BBB, molecular mechanisms underlying Aβ-RAGE interaction-induced BBB alterations are largely unknown. We found enhanced permeability, decreased zonula occludin-1 (ZO-1) expression and increased intracellular calcium and MMP secretion in endothelial cells exposed to Aβ(1–42). Aβ-induced changes in ZO-1 were attenuated by neutralizing antibodies against RAGE and inhibitors of calcineurin (CaN) and MMPs, suggesting that Aβ-RAGE interactions disrupt tight junction proteins via the Ca(2+)-CaN pathway. We also 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 of AD. These results identify a potential molecular pathway underlying Aβ-RAGE interaction-induced breakage of BBB integrity.