GSK-3b-Nrf2 Signaling Pathway as a Neuroprotective Mechanism in Alzheimer’s Disease

Abstract

β-Amyloid peptide (Aβ) is the major component of senile plaques accumulated in the brains of patients with Alzheimer’s disease (AD) and has been reported to cause neuronal cell death via oxidative stress. Therefore, attention has been focused on identifying redox-sensitive transcription factors and their target genes protecting against Aβ- induced oxidative cell death. Nrf2 plays a pivotal role in the transcriptional regulation of antioxidant proteins and detoxification enzymes and blocks apoptosis caused by a wide array of death signals. Ectopic expression of Nrf2 rescued cells from Aβ-induced cytotoxicity, apoptosis, intracellular accumulation of reactive oxygen species and oxidative damages. Moreover, Nrf2 overexpression increased the expression of γ-glutamylcysteine ligase (GCL), a rate-limiting enzyme in cellular glutathione biosynthesis and heme oxygenase-1 (HO-1), a key enzyme in heme degradation process. Conversely, knockdown of Nrf2 gene expression with siRNA or dominant negative mutant Nrf2 exacerbated Aβ-induced oxidative cell death. To further elucidate the upstream regulator for Nrf2 activation, we have focused on glycogen synthase kinase-3β (GSK-3β). Inhibition of Ab-induced GSK-3β activation by pharmacological inhibitors such as LiCl led to nuclear accumulation Nrf2 and transcriptional activation of Nrf2 downstream target genes and protected against Aβ-mediated oxidative cell death. In another experiment, some dietary and medicinal phytochemicals attenuated Aβ-induced oxidative cell death via suppression of GSK-3β and subsequent activation of Nrf2. Taken together, these findings suggest that GSK-3β-Nrf2 signaling pathway may act as a survival mediator against AD.