Fig. 8.

Schematic diagram of the role of LA in inhibiting Tau phosphorylation and neuronal loss including ferroptosis. Under Tau overexpression and hyperphosphorylated conditions, P301S mice developed iron overload. After LA administration, TFR expression level was downregulated while Fpn1 level was upregulated, thereby reducing the iron overload. Thus, iron overload-induced mitochondrial dysfunction and Ca²⁺ overload were not sufficient to induce calpain overactivation. p-P38, P25, and p-CDK5 levels were decreased and p-GSK3β level was increased, thereby inhibiting the hyperphosphorylation of Tau and Tau-induced iron overload. In addition, LA inhibited ferroptosis not only by reducing iron overload but also via the upregulation of xCT and GPx4. Moreover, the inhibition of calpain decreased the level of cleaved caspase3, which is involved in apoptosis, thus neuronal loss was rescued through the inhibition of apoptosis and ferroptosis.