HNE, a reactive end product of lipid peroxidation, can bind to lysine residues by Michael addition to cause protein modification; Michael addition is an organic reaction in which a ketone or an aldehyde is converted to an enolate or an imine in the presence of a base (Esterbauer et al., 1991). HNE significantly alters the conformation of cortical synaptosomal membrane proteins, causing dysfunctional proteins (Subramaniam et al., 1997). Studies have shown that HNE is increased in AD brains (Markesbery and Lovell, 1998) and AD ventricular fluid (Lovell et al., 1997). HNE binds to and likely explains the loss of function of the major glutamate transporter in an AD brain (Lauderback et al., 2001). Because it is present in the AD system and because it causes dysfunctional proteins through oxidative modification, HNE may play a role in DNA oxidation in AD.

Our laboratory has hypothesized that HNE causes conformational changes to histones, thus altering their DNA binding capabilities. DNA damage in AD may result subsequent to the disruption of histone-DNA interactions. Furthermore, HNE binding to histones may block histone acetylation, thereby potentially altering both histone-DNA interactions and transcription factor penetration. These hypotheses are tested in various ways. Electron paramagnetic resonance (EPR) spin-labeling shows whether or not HNE binds to histones and changes their conformation. Disturbing the ionic strength should lessen the ionic histone-DNA interaction; thus, differing the physiological ionic conditions may show an effect of HNE on histone-DNA interaction. Gel electrophoresis is also used to analyze the effect of HNE on histone acetylation. A manuscript describing the results of this study is nearly ready for submission for peer-review (Drake et al., 2003).

Conclusions

Current research indicates that Alzheimer's disease (AD) arises due to neurodegeneration promoted by oxidative stress in the brain and the overproduction of amyloid b -peptide (A b ). This oxidative stress can take the form of protein oxidation, lipid peroxidation, or DNA oxidation, which confound normal brain processes by disrupting lipid structure, protein function, and DNA binding capabilities. Prevention hope lies in the use of antioxidants such as Vitamin E and public acknowledgment of the risk factors such as low education and linguistic capacities. Antioxidants like N-acetyl cysteine (NAC) also pose a future option for treatment.

Because of the increasing life span, the effects of aging and neurodegeneration are becoming more prominent in the population, with the potential to evolve into a public health crisis in the near future. Considerable research currently focuses on possible treatment pathways and preventive measures for neurodegenerative diseases like AD.

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