Oxidative stress is a key factor involved in the development and progression of
Alzheimer disease (AD), and it is well documented that
free radical oxidative damage, particularly of neuronal
lipids,
proteins,
nucleic acids, and
sugars, is extensive in brains of AD patients. The complex chemistry of
peroxynitrite has been the subject of intense study and is now evident that there are two principal pathways for
protein modification: the first one involves homolytic
hydroxyl radical-like chemistry that results in
protein-based carbonyls and the second involves electrophilic nitration of vulnerable side chains, in particular the electron-rich aromatic rings of Tyr and Trp. In the presence of buffering
bicarbonate,
peroxynitrite forms a CO(2) adduct, which augments its reactivity. Formation of
3-nitrotyrosine by this route has become the classical
protein marker specifically for the presence of
peroxynitrite.
Protein-based carbonyls can be detected by two methods: (i) derivatization with
2,4-dinitrophenylhydrazine (DNPH) and detection of the
protein-bound
hydrazones using an
enzyme-linked anti-2,4-dinitrophenyl antibody and (ii) derivatization with
biotin-hydrazide and detection of the
protein-bound acyl
hydrazone with
enzyme-linked
avidin or
streptavidin. Glycation of
proteins by reducing
sugars (Maillard reaction) results in a profile of time-dependent adduct evolution rendering susceptibility to oxidative elaboration. In addition, oxidative stress can result in oxidized
sugar derivatives which can subsequently modify
protein through a process known as glycoxidation. Of more general importance, oxidative stress results in lipid peroxidation and the production of a range of electrophilic and mostly bifunctional
aldehydes that modify numerous
proteins. The more important
protein modifications are referred to as
advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs).
Protein modification can result in both non-cross-link and cross-link AGEs and ALEs, the latter arising from the potential bifunctional reactivity, such as that of the
lipid-derived modifiers
4-hydroxy-2-nonenal (HNE) and
malondialdehyde (MDA). Oxidative damage to
nucleic acids results in base modification, substitutions, and deletions. Among the most common modifications,
8-hydroxyguanosine (8OHG) is considered a signature of oxidative damage to
nucleic acid.Cells are not passive to increased
oxygen radical production but rather upregulate protective responses. In
neurodegenerative diseases,
heme oxygenase-1 (HO-1) induction is coincident with the formation of neurofibrillary tangles. This
enzyme that converts
heme, a prooxidant, to
biliverdin/
bilirubin (
antioxidants) and free
iron has been considered an
antioxidant enzyme. But seen in the context of arresting apoptosis, HO-1 and tau may play a role in maintaining the neurons free from the apoptotic signal (
cytochrome c), since tau has strong
iron-binding sites. Given the importance of
iron as a catalyst for the generation of
reactive oxygen species, changes in
proteins associated with
iron homeostasis can be used as an index of cellular responses. One such class of
proteins is the
iron regulatory proteins (IRPs) that respond to cellular
iron concentrations by regulating the translation of
proteins involved in
iron uptake, storage, and utilization. Therefore, IRPs are considered to be the central control components of cellular
iron concentration.