Neuroprotective strategies involving ROS in Alzheimer disease

Abstract

Alzheimer disease (AD) is a neurodegenerative disorder in which oxidative stress is a key hallmark. It occurs early in disease pathogenesis and can exacerbate its progression. Several causes of oxidative stress have been determined over the years. First, mitochondria play an important role in the generation and accumulation of free radicals. In addition to mitochondria, inflammation can also induce oxidative damage, especially via microglia, and microglia are also important for Aβ clearance. In AD, both mitochondrial function and inflammatory response are affected, leading to increased ROS formation and oxidative damage to lipid, proteins, and nucleic acids. Some other sources have also been identified. From these findings, various neuroprotective strategies against ROS-mediated damages have been elaborated in AD research. This review recapitulates some of the major strategies used to prevent oxidative stress and disease progression. Outcomes from in vitro and in vivo studies using models of AD are encouraging. However, only a few clinical trials have provided positive results in terms of slowing down cognitive decline. Nonetheless, there is still hope for improved compounds that would better target pathways implicated in ROS production. In fact, facilitating the endogenous antioxidant system by modulating transcription has great promise for AD therapy.

Figure 1. Scheme of the generation and role of free radicals in AD

In cells, free radicals can be generated by 2 major sources: mitochondria and NAPDH oxidase. Several key players, such as metals and/or Aβ can exacerbate their production. Once accumulating inside the cells, free radicals can cause lipid, protein, DNA and RNA damage that can exacerbate AD pathogenesis.

Figure 2. Mitochondria and ROS

(A) Scheme of the mitochondrial electron transport chain. Electrons are transferred from complex I (C-I) to complex IV (C-IV), including coenzyme Q10 (Q) and cytochrome c (Cyt c). (B) Scheme of mitochondria-mediated ROS from the complex I (C-I), complex II (C-II), and III (C-III) and from the tricarboxylic acid cycle (TCA). (C) Chemical reactions for the generation of reactive oxygen species (ROS) such as superoxide (O₂⁻), hydrogen peroxide (H₂O₂), reactive nitrogen species (RNS) such as peroxynitrite, and the chemistry of the Fenton reaction, which generates OH⁻ radicals.

Figure 3. Chemical structures of antioxidants

Figure 4. NADPH oxidase and production of ROS

The assembly of NADPH oxidase subunits (gp91^phox/p22^phox) with cytolosic subunits p47^phox, p40^phox, p67^phox and rac results in the active enzyme responsible for the generation of superoxide.

Figure 5. Antioxidant strategies in AD