Fig. 1

Metal ions imbalance in Alzheimer-like neurodegeneration and cognitive deficits. The metal ions (Fe, Cu, Zn and Ca) imbalance induces oxidative stress demonstrated by the reduced level/activity of GSH, SOD1 and ATOX1 and an increased level of ROS. Oxidative stress can induce tau hyperphosphorylation by activating protein kinases (such as GSK-3β, CDK5, MAPK, etc.) and/or inhibiting PP2A; it can also promote Aβ overproduction by activating β- and γ-secretases and/or inhibiting α-secretase. Together with the imbalanced metal ions and oxidative stress, or independently, the hyperphosphorylated tau (p-tau) and overproduced Aβ could induce ER stress, mitochondrial dysfunction, and autophagic impairments, leading to p-tau and Aβ aggregation and accumulation. Again, together with p-tau/Aβ accumulation, autophagic/mitochondrial deficits, ER stress and oxidative stress, or independently, the imbalanced metal ions can induce synapse damages, which causes synaptic dysfunction, neurodegeneration, and eventually learning and memory deficits. As indicated in the figure by the double-sided arrows, many of these pathological processes occur in a bi-directional way and thus form a vicious cycle during the age-dependent chronic neurodegeneration, such as seen in AD