4-HYDROXYNONENAL-DERIVED ADVANCED LIPID-PEROXIDATION END-PRODUCTS AREINCREASED IN ALZHEIMERS-DISEASE

Recent studies have demonstrated oxidative damage is one of the salien t features of Alzheimer's disease (AD). In these studies, glycoxidatio n adduction to and direct oxidation of amino acid side chains have bee n demonstrated in the lesions and neurons of AD. To address whether li pid damage may also play an important pathogenic role, we raised rabbi t antisera specific for the lysine-derived pyrrole adducts formed by l ipid peroxidation-derived 4-hydroxynonenal (HNE). These antibodies wer e used in immunocytochemical evaluation of brain tissue from AD and ag e-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 dystroph ic neurites were weakly stained, whereas the amyloid-beta deposits wer e unlabeled. Age-matched controls showed only background HNE-pyrrole i mmunoreactivity in hippocampal or cortical neurons. In addition to pro viding further evidence that oxidative stress-related protein modifica tion is a pervasive factor in AD, the known neurotoxicity of HNE sugge sts that lipid peroxidation may also play a role in the neuronal death in AD that underlies cognitive deficits.