Potential Role of Acrolein in Neurodegeneration and in Alzheimers Disease

Dang      Thanh Nam; Madeleine      Arseneault; Ven      Murthy; Charles      Ramassamy

doi:10.2174/1874467211003020066

Abstract

Lipid peroxidation leads to the formation of a number of aldehydes by-products, including acrolein. The most abundant aldehydes are 4-hydroxy-nonenal (4-HNE) and malondialdehyde (MDA) while acrolein is the most reactive. In Alzheimers brain, acrolein was found to be elevated in hippocampus and temporal cortex where oxidative stress is high. In late onset Alzheimers disease (AD), a 2-fold increase in levels of acrolein/guanosine adducts in nDNA was isolated from the hippocampus of AD as compared to age-matched control. These adducts are biologically relevant in that they may promote DNA – DNA and DNA – protein cross-linking while 4-HNE/guanosine adducts in nDNA were not elevated in AD. In AD, the activity of the glutathione-S-transferase, the main enzyme responsible for the detoxification of acrolein is significantly decreased in hippocampus. On neuronal primary culture from hippocampus, acrolein caused cell death and its toxicity is higher than 4-hydroxynonenal. Acrolein could modulate tau phosphorylation through different pathways. Acrolein has been shown to inhibit the mitochondrial activity. Due to its high reactivity, acrolein is not only a marker of lipid peroxidation but also an initiator of oxidative stress by adducting cellular nucleophilic groups found on proteins, lipids, and nucleic acid. As a strong electrophile molecule, acrolein can react about 110-150 times faster with the thiol group of cysteine than with 4-hydroxynonenal and decrease the level of the antioxidant glutathione. Taken together, these reactions suggest that acrolein could play a role in the pathophysiology of AD. In this review, we will summarize some mechanisms implicated in the toxicity of this by-product of lipid peroxidation in brain and their implication in AD.

Keywords: Alzheimer's disease, glutathione, polyamines, S-glutathionylation, redox potential