Copper chelators promote nonamyloidogenic processing of Aβ PP via MT 1/2 / CREB ‐dependent signaling pathways in Aβ PP / PS 1 transgenic mice

• Published in: Journal of pineal research 2018-10, Vol.65 (3)
• Main Authors: Wang, Zhuo, Zhang, Ya‐Hong, Zhang, Wei, Gao, Hui‐Ling, Zhong, Man‐Li, Huang, Ting‐Ting, Guo, Rui‐Fang, Liu, Na‐Na, Li, Dan‐Dan, Li, Yin, Wang, Zhan‐You, Zhao, Pu
• Format: Article
• Language: English
• ISSN: 0742-3098; 1600-079X
• DOI: 10.1111/jpi.12502

Copper is essential for the generation of reactive oxygen species ( ROS ), which are induced by amyloid‐β (Aβ) aggregation; thus, the homeostasis of copper is believed to be a therapeutic target for Alzheimer’s disease ( AD ). Although clinical trials of copper chelators show promise when applied in AD , the underlying mechanism is not fully understood. Here, we reported that copper chelators promoted nonamyloidogenic processing of Aβ PP through MT 1/2 / CREB ‐dependent signaling pathways. First, we found that the formation of Aβ plaques in the cortex was significantly reduced, and learning deficits were significantly improved in Aβ PP / PS 1 transgenic mice by copper chelator tetrathiomolybdate ( TM ) administration. Second, TM and another copper chelator, bathocuproine sulfonate ( BCS ), promoted nonamyloidogenic processing of Aβ PP via inducing the expression of ADAM 10 and the secretion of sA β PP α. Third, the inducible ADAM 10 production caused by copper chelators can be blocked by a melatonin receptor ( MT 1/2 ) antagonist (luzindole) and a MT 2 inhibitor (4‐P‐ PDOT ), suggesting that the expression of ADAM 10 depends on the activation of MT 1/2 signaling pathways. Fourth, three of the MT 1/2 ‐downstream signaling pathways, Gq/ PLC / MEK / ERK / CREB , Gs/ cAMP / PKA / ERK / CREB and Gs/ cAMP / PKA / CREB , were responsible for copper chelator‐induced ADAM 10 production. Based on these results, we conclude that copper chelators regulate the balance between amyloidogenic and nonamyloidogenic processing of Aβ PP via promoting ADAM 10 expression through MT 1/2 / CREB ‐dependent signaling pathways.