Implications of PI3K/AKT/PTEN Signaling on Superoxide Dismutases Expression and in the Pathogenesis of Alzheimer's Disease

Abstract

Alzheimer’s disease is a neurodegenerative sickness, where the speed of personal disease progression differs prominently due to genetic and environmental factors such as life style. Alzheimer’s disease is described by the construction of neuronal plaques and neurofibrillary tangles composed of phosphorylated tau protein. Mitochondrial dysfunction may be a noticeable feature of Alzheimer’s disease and increased production of reactive oxygen species has long been described. Superoxide dismutases (SODs) protect from excess reactive oxygen species to form less reactive hydrogen peroxide. It is suggested that SODs can play a protective role in neurodegeneration. In addition, PI3K/AKT pathway has been shown to play a critical role on the neuroprotection and inhibiting apoptosis via the enhancing expression of the SODs. This pathway appears to be crucial in Alzheimer’s disease because it is related to the tau protein hyper-phosphorylation. Dietary supplementation of several ordinary compounds may provide a novel therapeutic approach to brain disorders by modulating the function of the PI3K/AKT pathway. Understanding these systems may offer a better efficacy of new therapeutic approaches. In this review, we summarize recent progresses on the involvement of the SODs and PI3K/AKT pathway in neuroprotective signaling against Alzheimer’s disease.

Keywords: AKT; Alzheimer’s disease; PI3K; PPAR; PTEN; n-3 PUFAs; reactive oxygen species; superoxide dismutase.

Figure 1

Hypothetical schematic image of the pathogenesis pathway for Alzheimer’s disease is shown. Inflammation trigger, amyloid-β, X-ray, and UV irradiation all contribute to the ROS formation. The uncontrolled generation of ROS and oxidative stress mediated by inflammation and/or amyloid-β might contribute to neuron apoptosis via the hyper-phosphorylation of tau protein. Note that some critical pathways such as NADPH oxidase activation have been omitted for clarity.

Figure 2

Schematic localization of human SOD1, SOD2, and SOD3 are compartmentalized (SOD1, cytoplasm; SOD2, in the mitochondria; SOD3, in the extracellular space). The lightning bolts show the oxidative attack of ROS on macromolecules such as proteins, lipids, and DNAs.

Figure 3

Implication of SODs in the neuroprotection against Alzheimer’s disease via the signaling of PI3K/AKT/PTEN/GSK-3β pathway, and examples of molecules known to act on the regulatory pathways are shown. PI3K/AKT/PTEN/GSK-3β pathway and SODs may contribute to neuroprotection in AD. Hammerheads mean inhibition. Note that some critical events have been omitted for clarity