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Metal ion imbalance and oxidative stress trigger the overproduction of A by activating - or -secretases and inhibiting -secretase, and also cause tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3 (GSK-3), cyclin-dependent protein kinase-5 and MAPKs, and inhibiting protein phosphatase 2A (Wang et al., 2020)