Abstract
Alzheimer’s disease (AD), characterized by accumulation of amyloid-beta protein (Aβ) in brain parenchyma, is closely associated with brain ischemia. Decreased clearance of Aβ from brain is the main cause of Aβ accumulation in sporadic AD. However, the mechanisms underlying ischemia-mediated AD pathogenesis remain unclear. The receptor for advanced end glycation products (RAGE) and low-density lipoprotein receptor-related protein-1 (LRP-1) expressed at blood brain barrier (BBB) are actively involved in Aβ clearance. RAGE is thought to be a primary transporter of Aβ across BBB into the brain from the systemic circulation, while LRP-1 mediates the transport of Aβ out of the brain. Ginkgo biloba extract EGb761, a traditional Chinese medicine, has been widely used in the treatment of AD. To investigate the effects of EGb761 on the expression of RAGE and LRP-1 in endothelial cells in response to ischemic injury, we cultured bEnd.3 cells, an immortalized mouse cerebral microvessel endothelial cell line, under a chronic hypoxic and hypoglycemic condition (CHH) to mimic ischemic injury of BBB, and then treated with EGb 761. We found that EGb 761 markedly ameliorated the damage (evaluated by MTT assay) from CHH. Moreover, we demonstrated that CHH led to a significant increase in the expression of RAGE both at the mRNA and protein levels at all times (24, 36, and 48 h), conversely; CHH induced a dramatic decrease in LRP-1 mRNA and protein expression at both 36 and 48 h. The results indicated that CHH has differential effects on the expression of RAGE and LRP-1. Furthermore, EGb761 significantly reversed CHH-induced upregulation of RAGE expression and downregulation of LRP-1 expression. Our findings suggest that EGb761 favor clearance of Aβ via regulating the expression of RAGE and LRP-1 during brain ischemia. This may provide a new insight into a possible molecular mechanism underlying brain ischemia-mediated AD pathogenesis, and potential therapeutic application of EGb 761 in treatment of AD.
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We thank Shanghai Medical College, Fudan University for supplying bEnd.3 cell lines. This work was supported by a research grant from Natural Science Foundation of Southeast University (grant no: XJ0590215).
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Yan, FL., Zheng, Y. & Zhao, FD. Effects of ginkgo biloba extract EGb761 on expression of RAGE and LRP-1 in cerebral microvascular endothelial cells under chronic hypoxia and hypoglycemia. Acta Neuropathol 116, 529–535 (2008). https://doi.org/10.1007/s00401-008-0435-6
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DOI: https://doi.org/10.1007/s00401-008-0435-6