Model for One Aspect of Oxidative Stress in Alzheimer ’s Disease Brain: Lipid Peroxidation End Product, HNE, Binds to and Alters the Conformation and Function of Histones

Robin Theresa Petroze
University of Kentucky

Alzheimer’s disease (AD) is a neurodegenerative disorder that currently affects close to five million Americans. An oxidatively stressed system, characterized by an imbalance in pro-oxidant over anti-oxidant factors, AD brain has been shown to be susceptible to protein and lipid peroxidation by free radicals. Histones and DNA have been shown to be susceptible to oxidative stress in AD as well. In compacting into chromatin, DNA winds around an octamer of core histones. These histones are rich in lysines in the N-terminus, allowing for close interaction with DNA and adjacent nucleosomes. Histone acetylation weakens these interactions, allowing for the chromatin to open up to transcriptional factors. 4-hydroxy-2-trans-nonenal (HNE) is a reactive end product of lipid peroxidation that can bind to lysine residues by Michael addition to cause protein modification. Using electron paramagnetic resonance (EPR), we have shown that HNE binds to histones, changing their conformation. Gel electrophoresis shows that HNE binding to histones disrupts histone acetylation. Implications for AD are discussed with these results.