Common Protective Strategies in Neurodegenerative Disease: Focusing on Risk Factors to Target the Cellular Redox System

Abstract

Neurodegenerative disease is an umbrella term for different conditions which primarily affect the neurons in the human brain. In the last century, significant research has been focused on mechanisms and risk factors relevant to the multifaceted etiopathogenesis of neurodegenerative diseases. Currently, neurodegenerative diseases are incurable, and the treatments available only control the symptoms or delay the progression of the disease. This review is aimed at characterizing the complex network of molecular mechanisms underpinning acute and chronic neurodegeneration, focusing on the disturbance in redox homeostasis, as a common mechanism behind five pivotal risk factors: aging, oxidative stress, inflammation, glycation, and vascular injury. Considering the complex multifactorial nature of neurodegenerative diseases, a preventive strategy able to simultaneously target multiple risk factors and disease mechanisms at an early stage is most likely to be effective to slow/halt the progression of neurodegenerative diseases.

Figure 1

Contribution of inflammation, oxidative damage, and reduction in NT levels to neurodegeneration in aged brain after injury.

Figure 2

The vicious circle of the principal pathways involved in RAGE activation. AGE-RAGE binding activates different signalling pathways, in particular MAPK, PI3K, and NOX2, inducing inflammation, apoptosis, and oxidative stress. Moreover, the increased levels of NF-κB induced the expression of RAGEs. The inflammatory response is also enhanced by the disruption of tight junctions at NVU that compromises also the BBB integrity. Oxidative stress is increased also by the high level of NF-κB and by the consequent increment of MMP2-9. In aging, elevated ROS levels are not efficiently counteracted by endogenous antioxidative defences, and, as a consequence, AGE formation is increased. AGEs not only stabilize Aβ oligomers and NFT but also increase their formation. In addition, Aβ oligomers can also bind RAGE and activate the inflammatory/oxidative cascade. Finally, Aβ oligomers can trigger the impairment of mitochondrial ALDH2, leading to endothelial dysfunction and BBB leakage.