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.Nevertheless, 5-LOX is expressed in neurons,including the hippocampus, and its expression may increase with age (Sugaya et al.,2000).One autopsy-based study has associated increased activity in 12/15-LOXpathways with late-stage AD (Pratico et al., 2004).4 The Epoxygenase SystemIn addition to the COX and LOX pathways described above, AA and other PUFA sare substrates for enzyme-catalyzed oxidation by cytochome P450 s, the epoxyge-nase pathway.While the biological role for these eicosanoid products is less clear 118 K.Andreasson and T.J.Montinethan products of COX or LOX, there is growing evidence that at least some prod-ucts in this pathway play important roles in vascular physiology (Fisslthaler et al.,1999).Along this line, it has been proposed that glial generation of oxygenatedlipids by this pathway functionally contributes to neurovascular coupling (Lovicket al., 2005; Metea and Newman, 2006).We are unaware of reports connecting thispathway to specific elements in the pathogenesis of neurodegenerative diseases.5 Non Enzymatic Metabolites for AA5.1 Free Radical Damage to AAA central hypothesis for the pathogenesis of several neurodegenerative diseases isthat increased free radical damage contributes to the initiation and progression ofdisease (Montine et al., 2002b).It is critical to note that unlike enzyme-catalyzedreactions described above, free radical damage is an indiscriminate process that willsimultaneously modify multiple targets including nucleic acid, protein, and lipids(Montine et al., 2003).PUFAs including AA are among the most vulnerable targetsfor free radical damage, a process termed lipid peroxidation (Porter et al., 1995).This complex process directly damages membranes and generates a number ofoxygenated products that can be classified as either chemically reactive or stableproducts (Esterbauer and Ramos, 1996).5.1.1 Reactive Products of Lipid Peroxidation and Their BioactivityRecently, considerable progress has been made in understanding the potential con-tribution of chemically reactive products of lipid peroxidation to neurodegenera-tion.The presumed mechanism of action of all of these electrophilic products isadduction of nucleophilic groups in protein or nucleic acid.For example, adductionof a critical amino acid residue in an enzyme or transporter may lead to its dysfunc-tion (Esterbauer and Ramos, 1996; Keller et al., 1997; Mark et al., 1997).However,interpreting experiments that investigate the contribution of reactive products oflipid peroxidation to disease pathogenesis is limited by their lack of biochemicalspecificity.Despite this limitation to understanding the precise biochemical mechanisms ofaction, many studies in a variety of model systems and autopsy-derived tissue haveimplicated reactive products of lipid peroxidation in the pathogenesis of AD (Andoet al., 1998; Lovell et al., 1997; Markesbery and Lovell, 1998; McGrath et al., 2001;Montine et al., 1997, 1998; Sayre et al., 1997).One class of chemically reactiveproducts of lipid peroxidation that has been studied in great detail is diffusible lowmolecular weight aldehydes.By far, the most extensively studied of these are4-hydroxy-2-nonenal (HNE), generated by peroxidation of É-6 PUFAs like AA Arachidonic Acid Metabolites 119(Esterbauer et al., 1991).While the pathophysiologic consequences of overproduc-tion of HNE have been highlighted in numerous studies, it is noteworthy that thesereactive aldehydes also are generated at low levels in all cells and appear to have arole in normal physiologic signaling (Forman and Dickinson, 2004).Indeed, sev-eral highly polymorphic enzyme systems have evolved apparently to metabolizespecifically these lipid peroxidation products and thereby terminate their signalingor detoxify them (Picklo et al., 2002); two of these have been tentatively associatedwith an increased risk of AD (Kamino et al., 2000; Li et al., 2003).Recently,another class of chemically reactive lipid peroxidation products has been identified:³-ketoaldehyde isoketals (IsoKs) derived from AA (Bernoud-Hubac et al., 2001).These ³-ketoaldehydes are much more reactive with cellular nucleophiles thanHNE and, unlike the structurally similar COX-derived levuglandins, IsoKs remainesterified to phospholipids.In light of the ability of LGs to significantly accelerateoligomerization of A² peptides in vitro (Boutaud et al., 2002), IsoKs are now beingexplored for related mechanisms of neurotoxicity (Davies et al., 2002).5.1.2 Stable Products of Lipid Peroxidation and Their BioactivityIn the early 1990 s, Morrow and colleagues demonstrated that free radical-mediateddamage to AA followed by oxygen insertion and cyclization generated productsthat were isomeric to PG products of COX.These newly discovered compoundswere termed isoprostanes (IsoPs) (Morrow et al., 1990).There are three importantdifferences between PGs and IsoPs.First, IsoPs are a large class of molecules con-sisting of 64 enantiomers contained within four regioisomeric families.Second,IsoPs are formed in situ while esterified to phospholipids and may be subsequentlyreleased by hydrolysis.Third, while some IsoPs do activate G protein-coupledreceptors, the extent of their receptor-mediated activity remains unclear.What isclear is that predicting receptor activity based on similarity to isomeric PGs is lim-ited.Since the discovery of potent renal vasoconstrictor activity for 15-F2t-IsoP,there has been an explosion of interest in the PG receptor-mediated activity ofIsoPs, especially effects of 15-F2t-IsoP in vasculature, kidney, lungs, and platelets(Morrow and Roberts, 1997).Much of the receptor-mediated activity of 15-F2t-IsoPoccurs via TP (Audoly et al., 2000).The contribution of IsoP-mediated receptoractivation to neurodegenerative diseases is not known.5.1.3 Quantitative In vivo Biomarkers of Lipid PeroxidationA final aspect to consider for lipid oxidation products is their use as quantitativebiomarkers of free radical-mediated damage in vivo.Every lipid peroxidation prod-uct discussed above has been used as a measure of oxidative damage.Since wehave reviewed this topic recently, we will not go into great detail here, however, animportant point must be kept in mind (Montine et al., 2002b).The goal of a biomar-ker is to quantitatively reflect changes in free radical mediated damage.Interpretation 120 K.Andreasson and T.J.Montineof biomarkers that are chemically reactive or that are extensively metabolized hasinherent limitations
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