科研之友
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摘要
The reduced clearance of amyloid-beta peptide (A beta) from the brain partly accounts for the neurotoxic accumulation of A beta in Alzheimer's disease (AD). Recently, it has been suggested that P-glycoprotein (P-gp), which is an efflux transporter expressed on the luminal membrane of the brain capillary endothelium, is capable of transporting A beta out of the brain. Although evidence has shown that restoring P-gp reduces brain A beta in a mouse model of AD, the molecular mechanisms underlying the decrease in P-gp expression in AD is largely unknown. We found that A beta(1-42) reduced P-gp expression in the murine brain endothelial cell line bEnd.3, which was consistent with our in vivo data that P-gp expression was significantly reduced, especially near amyloid plaques in the brains of five familial AD mutations (5XFAD) mice that are used as an animal model for AD. A neutralizing antibody against the receptor for advanced glycation end products (RAGE) and an inhibitor of nuclear factor-kappa B (NF-kappa B) signaling prevented the decrease in A beta(1-42)-induced P-gp expression, suggesting that A beta reduced P-gp expression through NF-kappa B signaling by interacting with RAGE. In addition, we observed that the P-gp reduction by A beta was rescued in bEnd.3 cells receiving inductive signals or factors from astrocytes making contacts with endothelial cells (ECs). These results support that alterations of astrocyte-EC contacts were closely associated with P-gp expression. This suggestion was further supported by the observation of a loss of astrocyte polarity in the brains of 5XFAD mice. Taken together, we found that P-gp downregulation by A beta was mediated through RAGE-NF-kappa B signaling pathway in ECs and that the contact between astrocytes and ECs was an important factor in the regulation of P-gp expression.
- 出版日期2014-6
