Brain lipid peroxidation and alzheimer disease: Synergy between the Butterfield and Mattson laboratories

Abstract

Brains from persons with Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI), exhibit high levels of oxidative damage, including that to phospholipids. One type of oxidative damage is lipid peroxidation, the most important index of which is protein-bound 4-hydroxy-2-trans-nonenal (HNE). This highly reactive alkenal changes the conformations and lowers the activities of brain proteins to which HNE is covalently bound. Evidence exists that suggests that lipid peroxidation is the first type of oxidative damage associated with amyloid β-peptide (Aβ), a 38-42 amino acid peptide that is highly neurotoxic and critical to the pathophysiology of AD. The Butterfield laboratory is one of, if not the, first research group to show that Aβ42 oligomers led to lipid peroxidation and to demonstrate this modification in brains of subjects with AD and MCI. The Mattson laboratory, particularly when Dr. Mattson was a faculty member at the University of Kentucky, also showed evidence for lipid peroxidation associated with Aβ peptides, mostly in in vitro systems. Consequently, there is synergy between our two laboratories. Since this special tribute issue of Aging Research Reviews is dedicated to the career of Dr. Mattson, a review of some aspects of this synergy of lipid peroxidation and its relevance to AD, as well as the role of lipid peroxidation in the progression of this dementing disorder seems germane. Accordingly, this review outlines some of the individual and/or complementary research on lipid peroxidation related to AD published from our two laboratories either separately or jointly.

Keywords: Alzheimer disease; Amnestic mild cognitive impairment; Brain protein conformational and functional changes; HNE; Lipid peroxidation.

Figure 1.

Mechanism of Michael addition reaction of HNE with Cysteine to form a covalent adduct with this amino acid. Such reactions on proteins, including also potentially with His and Lys residues, changes the conformation of such proteins with consequent diminution or loss of function.

Figure 2.

Schematic diagram of hydrophobic Aβ oligomer inserting into the neuronal lipid bilayer, where lipid peroxidation takes place leading to formation of HNE. This highly reactive moiety then forms covalent adducts with membrane, cytosolic, and mitochondrial proteins, resulting in protein dysfunction and neuronal death. Cognitive loss is a consequence of neuronal death in key brain regions.

Figure 3.

Amino acid sequence of Aβ42 showing the generally hydrophobic nature of this peptide, which drives oligomers to solubilize in the lipid bilayer. Also shown are Aβ42 variants that were used to establish the critical importance of the helical conformation of the peptide in the lipid bilayer and the single methionine residue for the oxidative stress produced by Aβ(1-42) in in vitro [Aβ(1-42)I31P] (Kanski et al., 2002) and in in vivo [Aβ(1-42)M35L] (Butterfield et al., 2010) studies.

Figure 4.

Role of Methionine residue 35 in Aβ42-associated lipid peroxidation and HNE formation. After insertion into the lipid bilayer, Aβ42 oligomer, with its Met-35 residue, adopts an alpha-helical secondary structure with the latter’s i + 4 rule of amino acid interactions (highlighted as expanded view) showing that the O-atom of the peptide bond of Ile-31 is within a 3.7 Angstrom distance of the S-atom of Met-35. The greater electronegativity of O vs. S leads to one of the lone pairs of electrons on the S-atom being pulled toward the Ile-31’s O-atom, which causes less attraction of these electron to the protons in the S-atom nucleus and thereby making these electrons vulnerable to a one-electron oxidation by a radical R^. shown near the word “Start.” The resulting S^.+ radical immediately abstracts a nearby labile allylic H-atom from an unsaturated acyl chain of a lipid in the bilayer, leading to SH⁺ on Met and a C^. radical on the allylic carbon atom. The SH⁺, being an acid with pKa of −5, immediately loses the H⁺ to any base B, to regenerate Met. That is, this is a catalytic reaction in which Met starts and ends the reaction on the peptide. Meanwhile, because radical-radical reactions are among the fastest reactions known, the C^. radical on the allylic carbon atom immediately binds a paramagnetic oxygen molecule (there are 2 unpaired electrons on molecular oxygen), which has zero dipole moment and is therefore highly soluble in a hydrophobic environment like a lipid bilayer. The resulting COO^. lipid peroxyl radical abstracts another nearby labile allylic H-atom from an unsaturated acyl chain of a phospholipid to form the lipid hydroperoxide, COOH, and another C^. radical on the allylic carbon atom from which the second allylic H-atom was obtained. That is, this becomes a chain reaction that constantly repeats as long as there are present oxygen and sufficient number of unsaturated lipid acyl chains with allylic H-atoms. The lipid hydroperoxide is the moiety from which HNE is derived. Note that only a small amount of the original S^.+ radical needs to be formed, since a large amount of HNE will be formed from the chain reaction associated with lipid peroxidation. The nature of the initiating radical or other species are not known. This author speculates that either molecular oxygen (which results in superoxide formation after obtaining an electron from the S-atom of Met) or weakly-associated Cu²⁺ on Met is reduced to Cu⁺ , which would react by Fenton Chemistry with hydrogen peroxide to form the highly reactive ^.OH radical, are the most likely possibilities for formation of the S^.+ radical.

Figure 5.

Aβ42 oligomer-associated lipid peroxidation leads to inhibition of the low density-like receptor protein-1 (LRP-1), whose loss of function could contribute to brain accumulation of Aβ42 and resulting oxidative damage. In addition, Aβ42 oligomers are reportedly capable of initiating the PI3K/Akt/mTOR axis, with resulting insulin resistance and inhibition of autophagy. Similarly, Aβ42 oligomer-associated lipid peroxidation leads to HNE binding to and inhibition of the glutamate transporter, EAAT2 (also called Glt-1) in AD brain, likely contributing to excitotoxicity and neuronal death.

Figure 6.

Brains in persons with AD or MCI have elevated HNE-bound proteins compared to aged-matched controls. In the middle ring, various functional pathways are noted that are damaged secondary to covalent HNE binding to Cys, His, or Lys residues. Other processes and pathways also are affected. The outer ring indicates the resulting dysfunctions that are seen in AD and MCI brain as a consequence of HNE-bound proteins in the various pathways noted. See text for more details.