Copper chelators promote nonamyloidogenic processing of AβPP via MT_1/2/CREB‐dependent signaling pathways in AβPP/PS1 transgenic mice

Abstract

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 MT1/2/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 (MT1/2) antagonist (luzindole) and a MT2 inhibitor (4‐P‐PDOT), suggesting that the expression of ADAM10 depends on the activation of MT1/2 signaling pathways. Fourth, three of the MT1/2‐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 MT1/2/CREB‐dependent signaling pathways.

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

“…Furthermore, Cu 2+ significantly affects the amyloid cascade, by which it interacts with APP through a Cu 2+ -binding domain [49]. Copper chelator can inhibit the activity of β-secretase [50]. In a preclinical AD model, small amounts of copper in drinking water can induce Aβ accumulation and significantly retard the learning ability [51].…”

Activation of CREB‐mediated autophagy by thioperamide ameliorates β‐amyloid pathology and cognition in Alzheimer’s disease

“…Our previous study has showed that H3R antagonist activates autophagy and protects against cerebral ischemic injury (Yan et al, 2014). In addition, activation of H3R downstream signaling CREB, which is involved in improving cognitive dysfunction and Aβ pathology in AD (Wang et al, 2018; Yin et al, 2016), could also up‐regulate autophagy (Chong et al, 2018; Liu et al, 2019; Seok et al, 2014). Nevertheless, whether CREB‐mediated autophagy is involved in the alleviated cognitive deficit and Aβ pathology by H3R antagonist in AD remains undetermined.…”

Inhibition of copper transporter 1 prevents α-synuclein pathology and alleviates nigrostriatal degeneration in AAV-based mouse model of Parkinson's disease

“…After the samples returned to room temperature, they were diluted 20 times with 0.1% nitric acid (Sigma). Then, the samples were measured using AAS (ZEEnit700P, Analytikjena, Germany) as previously described [ 58 ].…”