Evidence against a role of P-glycoprotein in the clearance of the Alzheimer's disease Aβ1-42 peptides

It has been proposed that the amyloid-beta peptides (A beta) cause the neuronal degeneration in the Alzheimer's disease brain. An imbalance between peptide production at the neuronal level and their elimination across the blood-brain-barrier (BBB) results in peptide accumulation inside the brain. The identification and functional characterization of the transport systems in the BBB with the capacity to transport A beta is crucial for the understanding of A beta peptide traffic from the brain to the blood. In this context, it has been suggested that the P-glycoprotein (P-gp), expressed in endothelial cells of the BBB, plays a role in the elimination of A beta. However, there is little, if any, experimental evidence to support this; therefore, the aim of this investigation was to determine whether P-gp is capable of transporting A beta peptides. Our results show that ATPase activity measured in plasma membrane vesicles of K562 cells overexpressing P-gp is not increased by the presence of A beta(42), suggesting that A beta(42) is not a P-gp substrate. Similarly, P-gp of pirarubicin was unaffected by A beta(42). Moreover, the overexpression of P-gp does not protect cells against A beta(42) toxicity. Taken together, our results support the conclusion that A beta(42) is not transported by P-gp.