4‐Hydroxynonenal‐Derived Advanced Lipid Peroxidation End Products Are Increased in Alzheimer's Disease

TLDR

Oxidative damage, including glycoxidation and direct oxidation of amino acid side chains, is a prominent feature of Alzheimer’s disease lesions and neurons. The study aimed to determine whether lipid peroxidation–derived 4‑hydroxynonenal (HNE) contributes to AD pathology. Rabbit antisera specific for HNE‑derived lysine pyrrole adducts were generated and applied in immunocytochemical analysis of AD and age‑matched control brain tissue. HNE‑pyrrole immunoreactivity was detected in roughly half of neurofibrillary tangles and in neurons without tangles, but was largely absent from senile plaques and amyloid‑β deposits, and only background staining appeared in controls, supporting a role for lipid peroxidation in AD‑related neuronal death.

Abstract

Abstract: Recent studies have demonstrated oxidative damage is one of the salient features of Alzheimer's disease (AD). In these studies, glycoxidation adduction to and direct oxidation of amino acid side chains have been demonstrated in the lesions and neurons of AD. To address whether lipid damage may also play an important pathogenic role, we raised rabbit antisera specific for the lysine‐derived pyrrole adducts formed by lipid peroxidation‐derived 4‐hydroxynonenal (HNE). These antibodies were used in immunocytochemical evaluation of brain tissue from AD and age‐matched control patients. HNE‐pyrrole immunoreactivity not only was identified in about half of all neurofibrillary tangles, but was also evident in neurons lacking neurofibrillary tangles in the AD cases. In contrast, few senile plaques were labeled, and then only the dystrophic neurites were weakly stained, whereas the amyloid‐β deposits were unlabeled. Age‐matched controls showed only background HNE‐pyrrole immunoreactivity in hippocampal or cortical neurons. In addition to providing further evidence that oxidative stress‐related protein modification is a pervasive factor in AD, the known neurotoxicity of HNE suggests that lipid peroxidation may also play a role in the neuronal death in AD that underlies cognitive deficits.