Involvements of the lipid peroxidation product, HNE, in the pathogenesis and progression of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. A number of hypotheses have been proposed to explain AD pathogenesis. One such hypothesis proposed to explain AD pathogenesis is the oxidative stress hypothesis. Increased levels of oxidative stress markers including the markers of lipid peroxidation such as acrolein, 4-hydroxy-2-trans-nonenal (HNE), malondialdehyde, etc. are found in brains of AD subjects. In this review, we focus principally on research conducted in the area of HNE in the central nervous system (CNS) of AD and mild cognitive impairment (MCI), and further, we discuss likely consequences of lipid peroxidation with respect to AD pathogenesis and progression. Based on the research conducted so far in the area of lipid peroxidation, it is suggested that lipid accessible antioxidant molecules could be a promising therapeutic approach to treat or slow progression of MCI and AD.

Figure 1. Involvement of Met-35 of Aβ(1-42) in lipid peroxidation

The S-atom of Met-35 of the Aβ(1-42) peptide can undergo one-electron oxidation to form a sulfuranyl radical cation within the bilayer, which has the ability to abstract a labile, allylic H-atom from the unsaturated acyl chains of lipid molecules, leading to initiation of lipid peroxidation processes [13, 14]. Like most integral membrane proteins, α-helical Aβ(1-42) adheres to the i+4 rule, causing the backbone carbonyl oxygen of Ile-31 on Aβ(1-42) to draw the electron density of the Met-35 S-atom toward itself, making the S-atom more vulnerable to oxidation and subsequent formation of the sulfuranyl radical cation. The sulfuranyl radical can, in turn, abstract allylic H-atoms from neighboring fatty acyl chains within the bilayer, forming a fatty acid carbon-centered free radical that can immediately bind paramagnetic, non-polar oxygen (O₂) to form a peroxyl free radical. The peroxyl radical then abstracts another labile H-atom from nearby fatty acyl chains, perpetuating the catalytic chain reaction initiated by Met-35 of the Aβ(1-42) peptide. Because Met-35 is inevitably reduced back to its starting state, this reaction can begin again, amplifying the neurotoxic affects of the Aβ(1-42) peptide within the cell.

Figure 2. Formation of 4-hydroxy-2-trans-nonenal (HNE) from arachidonic acid

The catalytic conversion of the Aβ(1-42) Met-35 S-atom to the sulfuranyl radical cation leads to the abstraction of a labile, allylic H-atom from unsaturated fatty acyl chains within the bilayer. In particular, arachidonic acid is a common fatty acid within the bilayer that is readily oxidized to produce one of the highly reactive lipid peroxidation products, HNE. Reactive oxygen species (ROS) other than Aβ(1-42) can also oxidize arachidonic acid to form a reactive hydroperoxide intermediate that is quickly converted to a peroxyl radical by Fe²⁺ (Fenton chemistry). The highly reactive peroxyl radical causes a molecular rearrangement which cyclizes the radical, arachidonic acid intermediate. Further oxidation and Fenton chemistry results in the β-scission of the cyclized intermediate, causing eventual formation of HNE.

Figure 3. 4-hydroxy-2-trans-nonenal (HNE) adduction of lysine, histidine, and cysteine

HNE is a membrane diffusible, highly reactive alkenal species (formed by oxidation of arachidonic acid) that can readily oxidize other biomolecules, contributing to AD neurotoxicity [19]. HNE can covalently binds to lysine, histidine, and cysteine residues of proteins via Michael addition, forming adducts that are known to change the structural conformation [21] and function of proteins [14, 22, 23]. Resultant HNE-adduct structures with Lys, His, and Cys are shown.