Linking multiple pathogenic pathways in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder presenting as progressive cognitive decline with dementia that does not, to this day, benefit from any disease-modifying drug. Multiple etiologic pathways have been explored and demonstrate promising solutions. For example, iron ion chelators, such as deferoxamine, are a potential therapeutic solution around which future studies are being directed. Another promising domain is related to thrombin inhibitors. In this minireview, a common pathophysiological pathway is suggested for the pathogenesis of AD to prove that all these mechanisms converge onto the same cascade of neuroinflammatory events. This common pathway is initiated by the presence of vascular risk factors that induce brain tissue hypoxia, which leads to endothelial cell activation. However, the ensuing hypoxia stimulates the production and release of reactive oxygen species and pro-inflammatory proteins. Furthermore, the endothelial activation may become excessive and dysfunctional in predisposed individuals, leading to thrombin activation and iron ion decompartmentalization. The oxidative stress that results from these modifications in the neurovascular unit will eventually lead to neuronal and glial cell death, ultimately leading to the development of AD. Hence, future research in this field should focus on conducting trials with combinations of potentially efficient treatments, such as the combination of intranasal deferoxamine and direct thrombin inhibitors.

Keywords: Alzheimer’s disease; Etiologies; Iron; Oxidative stress; Thrombin; Vascular risk factors.

Figure 1

The physiopathological pathways linking endothelial dysfunction and thrombin activation to the neurotoxic effects of iron ions through enhancement of the oxidative stress that leads to neuronal and glial cell death. Dark red ovals: Therapeutic agents; Light orange boxes: Pathophysiological mechanisms taking place in the vascular endothelium; Gray boxes: Pathological events observed in AD; Light yellow oval: Macrophages. AD: Alzheimer’s disease; DFO: Deferoxamine; HO-1: Heme oxygenase-1; ROS: Reactive oxygen species.