Copper chelators promote nonamyloidogenic processing of AβPP via MT_1/2 /CREB-dependent signaling pathways in AβPP/PS1...

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 AβPP 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 AβPP/PS1 transgenic mice by copper chelator tetrathiomolybdate (TM) administration. Second, TM and another copper chelator, bathocuproine sulfonate (BCS), promoted nonamyloidogenic processing of AβPP via inducing the expression of ADAM10 and the secretion of sAβPPα. Third, the inducible ADAM10 production caused by copper chelators can be blocked by a melatonin receptor (MT_1/2 ) antagonist (luzindole) and a MT₂ inhibitor (4-P-PDOT), suggesting that the expression of ADAM10 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 ADAM10 production. Based on these results, we conclude that copper chelators regulate the balance between amyloidogenic and nonamyloidogenic processing of AβPP via promoting ADAM10 expression through MT_1/2 /CREB-dependent signaling pathways.