Elevated levels of 4-hydroxynonenal-histidine Michael adduct in the hippocampi of patients with Alzheimer's disease

Abstract

Alzheimer's disease (AD) is among the most common causes of progressive cognitive impairment in humans and is characterized by neurodegeneration in the brain. Lipid peroxidation is thought to play a role in the pathogenesis of AD. 4-hydroxynonenal (HNE) results from peroxidation of polyunsaturated fatty acids and it in turn gives evidence of lipid peroxidation in vivo. HNE reacts with protein histidine residue to form a stable HNE-histidine Michael adduct. To clarify the influence of lipid peroxidation on the pathogenesis of AD, we measured HNE-histidine Michael adduct in hippocampi from four AD patients and four age-matched controls by means of semiquantitative immunohistochemistry using a specific antibody to cyclic hemiacetal type of HNE-histidine Michael adduct. This antibody does not react with the ring-opened form of HNE-histidine Michael adduct and the pyrrole form of HNE-lysine Michael adduct. The HNE adduct was detected in the hippocampi of both AD and control donors, especially in the CA2, CA3 and CA4 sectors. Immunoreactive intensity of HNE adduct in these sectors were significantly higher in AD patients than in the controls. The HNE adduct was found in the perikarya of pyramidal cells in the hippocampus. These results show that the hippocampi of patients with AD undergo lipid peroxidation and imply that this activity underlies the production of cytotoxic products such as HNE that are responsible for the pathogenesis of AD.The progressive cognitive impairment of Alzheimer's disease (AD) is associated with neuronal loss as well as the formation of neurofibrillary tangles (NFTs) and senile plaques in the brain (25). Free radical-mediated oxidative damage, energy depletion, deposition of amyloids and NFTs, excitotoxicity, and vascular endothelial cell damage are all thought to participate in the pathogenesis of AD (13). Oxygen-derived free radicals, byproducts of respiration, cause oxidative damage to cellular biomolecules including lipids, proteins and nucleic acids. The brain seems to be especially vulnerable to lipid peroxidation by free radicals, because it consumes approximately one-fifth of humans' oxygen intake, has a relative paucity of antioxidant systems and contains high concentrations of polyunsaturated fatty acids (PUFAs) (11). Lipid peroxidation results in structural damage to membranes and generation of secondary products such as reactive aldehydes

Original article Suppression of the lipid peroxidation process in the CNS reduces neurological expression of experimentally induced autoimmune encephalomyelitis

“…Malondialdehyde (MDA) is a small end product of the degradation of oxidized fatty acids, which can be used as a measure of the LP process. Although MDA and 4-hydroxy-2-nonenal are the major LP products, different fatty acids form specific products -other aldehydes, including oxidized phosphatidylcholine (OxPC), acrolein and isoprostanes during the LP process [7,8]. Free radi cal catalyzed peroxidation of the arachidonic acid, ester ified in membrane phospholipids, transform it into pro staglandinlike, but cyclooxygenase-independent, isoprostanes.…”

Immunochemical Detection of Lipid Hydroperoxide- and Aldehyde-Modified Proteins in Diseases

“…The pathology of AD is dominated by neuronal loss and the formation of amyloid-containing neuritic (senile) plaque and neurofibrillary tangles in the frontal cortex and hippocampus (Zarkovic 2003). Immunoreactive intensity of the HNE-histidine adduct in CA2, CA3 and CA4 sectors in the hippocampi was significantly higher in AD patients than in the controls (Fukuda et al 2009). Strong immunoexpression of acrolein-modified KLH occurred in more than half of the neurofibrillary tangles in AD patients (Calingasan et al 1999).…”

“…These results show that pyramidal neurons in these sectors of hippocampi and the neurofibrillary of AD patients are prone to undergo lipid peroxidation. The production of cytotoxic products such as HNE and acrolein may be responsible for the pathogenesis of AD (Fukuda et al 2009). …”

Neuroinflammation and demyelination from the point of nitrosative stress as a new target for neuroprotection

“…The indirect evidence of intensive oxidative stress in neuroinflammation are based on tracking concentrations of lipid peroxidation end-products during neuroinflammation (Fukuda et al, 2009;Miller et al, 2011). Some studies of demyelinating plaque have found the increased presence of low-density lipoprotein (LDL) molecules, modified by lipid peroxidation, in the very plaques, macrophages, and astrocytes, in parallel with the increase of the concentration of lipid peroxidation end-products (Hendrickx et al, 2013).…”