FIGURE 9.

A functional model of melatonin protecting effects against KA-induced neuronal tau hyperphosphorylation and memory deficits. KA treatment triggers ER stress and causes Ca²⁺ hike, leading to calpain activity upregulation. Upregulated calpain activity eventually results in the cleavage of p35 and GSK-3β, and tau hyperphosphorylation. Melatonin inhibits KA-induced GSK-3β and CDK5 activation and tau hyperphosphorylation via alleviating ER stress. Arrows indicate positive regulation, and blocks indicate negative regulation.