Ceramides in Alzheimer’s Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and Aβ Accumulation

Figure 3

Interplay between ceramides, Aβ and oxidative stress. Increased levels of ceramides directly increase levels of Aβ by increasing the half-life of BACE1 through posttranslational stabilization. As a positive feedback loop, the generated Aβ induces a further increase in ceramide levels by activating SMases activities in a ROS-dependent fashion. Aβ promotes accumulation of free radicals via NADPH oxidase activation and glutathione (GSH) depletion and induces membrane oxidative stress leading to generation of 4-hydroxynonenal (HNE), the neurotoxic product that exacerbates neuronal death through protein adduct formation, impairment of glucose metabolism, and ATP depletion.