Phosphorylation of Tau Protein as the Link between Oxidative Stress, Mitochondrial Dysfunction, and Connectivity Failure: Implications for Alzheimer’s Disease

Figure 3

The relationship between synaptic transmission, tau, and mitochondria. The intricate and close relationship between mitochondria and synaptic check points makes them potential therapeutic targets (red squares). Phosphorylated tau protein acts as a central connector between mitochondria and synaptic formations. Calcium (Ca²⁺) enters via NMDA receptors and this leads to activation of protein phosphatase 1 (PP1), a key enzyme in synaptically-induced LTD. PP1 can dephosphorylate GSK3β, leading to the activation of tau and NMDA receptor. Tau contributes to NMDA activation through the PSD95-Fyn complex. Importantly, GSK3β is also activated by Akt through mitochondrial pathways, suggesting a fine regulatory mechanism. During neurodegeneration, oxidative stress affects levels of tau phosphorylation and GSK3β; this breaks the fine balance that controls memory formation, therefore leading to synaptic failure.