Targeting Glycogen Synthase Kinase-3β for Therapeutic Benefit against Oxidative Stress in Alzheimer's Disease: Involvement of the Nrf2-ARE Pathway

Figure 1

Induction of the Nrf2-ARE pathway under normal and pathological conditions: potential role of GSK-3β as a negative regulator of Nrf2. (a) In normal conditions, actin-associated Keap1 sequesters Nrf2 in the cytosol and targets it for degradation. (b) Endogenously and exogenously generated ROS alter the interaction between Nrf2 and its repressor, resulting in the accumulation of Nrf2 in the cytoplasm. Nrf2 translocates into the nucleus. (c) An abundance of Nrf2 in the nucleus results in the binding of Nrf2 to the ARE and the increased expression of protective, Nrf2-controlled genes. (d) In conditions of prolonged oxidative stress, GSK-3β is activated. (e) Activated GSK-3β phosphorylates Fyn, causing nuclear translocation. (f) Nuclear Fyn phosphorylates Nrf2, leading to nuclear export of Nrf2 and degradation in the cytosol.