Lipid peroxidation triggers neurodegeneration: a redox proteomics view into the Alzheimer disease brain

Abstract

Lipid peroxidation involves a cascade of reactions in which production of free radicals occurs selectively in the lipid components of cellular membranes. Polyunsaturated fatty acids easily undergo lipid peroxidation chain reactions, which, in turn, lead to the formation of highly reactive electrophilic aldehydes. Among these, the most abundant aldehydes are 4-hydroxy-2-nonenal (HNE) and malondialdehyde, while acrolein is the most reactive. Proteins are susceptible to posttranslational modifications caused by aldehydes binding covalently to specific amino acid residues, in a process called Michael adduction, and these types of protein adducts, if not efficiently removed, may be, and generally are, dangerous for cellular homeostasis. In the present review, we focused the discussion on the selective proteins that are identified, by redox proteomics, as selective targets of HNE modification during the progression and pathogenesis of Alzheimer disease (AD). By comparing results obtained at different stages of the AD, it may be possible to identify key biochemical pathways involved and ideally identify therapeutic targets to prevent, delay, or treat AD.

Keywords: 4-Hydroxy-2-nonenal; ATP synthase; Collapsin regulatory protein 2; Enolase; Lipid peroxidation; Oxidative stress; Proteomics.

Figure 1

Chemical structure of 4-hydroxy-2-nonenal (HNE), malondialdehyde (MDA) and acrolein.

Figure 2

Lipid peroxidation process.

Figure 3

HNE reacts with proteins either via Michael adduct, Schiff base formation or both.

Figure 4

Putative scenario of the oxidative stress-induced modification HO-1 in AD hippocampus. (1) White arrows: increased oxidative stress levels in AD leads to oxidative modification of HO-1 (e.g. HNE) thus resulting in impairment of its functions. (2) Gray arrows: in response to oxidative stress, cell activates HO-1 by upregulating protein synthesis or by Ser-phosphorylation. At the same time, activated” HO-1 is a target of oxidative modifications. Impairment of HO-1 functions may contribute to exacerbate oxidative damage in AD.

Figure 5

Amyloid β-peptide (Aβ) is generated by proteolytic cleavage of amyloid precursor protein (APP) by the action of secretases. Once generated Aβ undergo aggregations and is eventually deposited extracellularly as senile plaques. Oligomeric Aβ can insert itself into the lipid bilayer, subsequently initiating the lipid peroxidation process leading to the formation of highly reactive products such as malondialdehyde (MDA), 4-hydroxy 2-trans nonenal (HNE), and acrolein. HNE can react with the proteins forming HNE-protein adducts consequently altering the function of proteins. During the progression of the Alzheimer’s disease (AD), enolase, hemeoxygenase-1 (HO-1), collapsing response mediated protein 2 (CRMP2), and ATP synthase alpha are selective modified by HNE, eventually leading to cellular impairment and AD pathogenesis.