Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier

The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-beta (A beta) peptide is a central event in the pathogenesis of Alzheimer's disease (AD). Whereas transport of A beta across the BBB can occur via transcellular endothelial receptors, the paracellular movement of A beta has not been described. We show that soluble human A beta(1-40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma A beta(1-40) levels were significantly increased, brain A beta(1-40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, A beta can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated A beta movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of A beta from the brain.