Glycerophospholipids and glycerophospholipid-derived lipid mediators: A complex meshwork in Alzheimer’s disease pathology

Progress in Lipid Research 50 (2011) 313–330

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Progress in Lipid Research journal homepage: www.elsevier.com/locate/plipres

Review

Glycerophospholipids and glycerophospholipid-derived lipid mediators: A complex meshwork in Alzheimer’s disease pathology Vincenza Frisardi a,⇑, Francesco Panza b, Davide Seripa b, Tahira Farooqui c, Akhlaq A. Farooqui c a

Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Bari, Italy Geriatric Unit and Gerontology, Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy c Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA b

a r t i c l e

i n f o

Article history: Received 9 June 2011 Received in revised form 9 June 2011 Accepted 9 June 2011 Available online 15 June 2011 Keywords: Glycerophospholipids Lipid mediators Arachidonic acid Docosahexaenoic acid Eicosanoids Docosanoids Endocannabinoids Lysophosphatidylcholine Platelet activating factor Diet Polyunsaturated fatty acids Dementia Alzheimer’s disease

a b s t r a c t An increasing body of evidence suggested that intracellular lipid metabolism is dramatically perturbed in various cardiovascular and neurodegenerative diseases with genetic and lifestyle components (e.g., dietary factors). Therefore, a lipidomic approach was also developed to suggest possible mechanisms underlying Alzheimer’s disease (AD). Neural membranes contain several classes of glycerophospholipids (GPs), that not only constitute their backbone but also provide the membrane with a suitable environment, fluidity, and ion permeability. In this review article, we focused our attention on GP and GP-derived lipid mediators suggested to be involved in AD pathology. Degradation of GPs by phospholipase A2 can release two important brain polyunsaturated fatty acids (PUFAs), e.g., arachidonic acid and docosahexaenoic acid, linked together by a delicate equilibrium. Non-enzymatic and enzymatic oxidation of these PUFAs produces several lipid mediators, all closely associated with neuronal pathways involved in AD neurobiology, suggesting that an interplay among lipids occurs in brain tissue. In this complex GP meshwork, the search for a specific modulating enzyme able to shift the metabolic pathway towards a neuroprotective role as well as a better knowledge about how lipid dietary modulation may act to slow the neurodegenerative processes, represent an essential step to delay the onset of AD and its progression. Also, in this way it may be possible to suggest new preventive or therapeutic options that can beneficially modify the course of this devastating disease. Ó 2011 Elsevier Ltd. All rights reserved.

Abbreviations: 2-AG, 2-arachidonoylglycerol; 4-HNE, 4-hydroxynonenals; 4-HHE, 4-hydroxyhexenal; AA, arachidonic acid; Ab, b-amyloid; ADAM, A Disintegrin And Metalloprotease; ADAPT, Alzheimer’s Disease Anti-inflammatory Prevention trial; AD, Alzheimer’s disease; AEA, arachidonyl-ethanolamide (anandamide); APP, amyloid precursor protein; BACE1, b-site APP cleavage enzyme; BAD, BCL-2-associated death promoter; BAX, BCL-2-associated X protein; BBB, blood–brain barrier; BCL-2, B-cell lymphoma 2; BDNF, brain-derived neurotrophic factor; CA1, cornu ammonius 1; CB1, cannabinoid receptors of type 1; CB2, cannabinoid receptors of type 2; CNS, central nervous system; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; DHA, docosahexaenoic acid; EC, endocannabinoid; EPA, eicosapentaenoic acid; EPOX, epoxygenases; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; FAAH, fatty acid amidohydrolase; GP, glycerophospholipid; CSF, cerebrospinal fluid; GSK-3, glycogen synthase kinase 3; HETE, hydroxyeicosatetraenoic acid; isoF, isofuran; isoK, isoketal; isoP, isoprostane; IL, interleukin; JNK/SAPK, c-Jun N-terminal kinase/ stress-activated protein kinase; LA, linoleic acid; LC-ESI-MS, liquid chromatography electrospray ionization mass spectrometry; LC-FACS, long-chain fatty acyl-CoA synthetase; LOX, lipoxygenases; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; LPI, lysophosphatidylinositol; LPS, lysophosphatidylserine; LT, leukotriene; LTP, long term potentiation; LX, lipoxin; MAPK, mitogen-activated protein kinase; MCI, mild cognitive impairment; MDA, malondialdehyde; mGluR, metabotropic glutamate receptor; MaR, maresin; NF-kB, nuclear factor-kappa B; NF, neurofuran; NFT, neurofibrillary tangle; NK, neuroketal; NMDA, N-methyl-D-aspartate; NMDAR, N-methyl-D-aspartate glutamate receptor subtype; NOS, nitric oxide synthase; NP, neuroprostane; NP, neuroprotectin; NSAID, nonsteroidal anti-inflammatory drug; PAF, platelet activating factor; PAFR, platelet activator factor receptor; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PKC, protein kinase C; PLA2, phospholipase A2; PG, prostaglandin; PI, phosphatidylinositol; PMN, polymorphonuclear neutrophils; PPAR, peroxisome proliferator-activated receptor; PUFA, polyunsaturated fatty acid; RAR, retinoic acid receptor; rCBF, regional cerebral blood flow; ROS, reactive oxygen species; RPE, retinal pigment epithelium; Rv, resolvin; RXR, retinoid X receptor; SP, senile plaque; sPLA2, secretory phospholipase A2; TNF-a, tumor necrosis factor-a; TRPV1, transient receptor potential vanilloid 1; TX, thromboxane. ⇑ Corresponding author. Address: Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Policlinico, Piazza Giulio Cesare, 11, 70124 Bari, Italy. E-mail address: [email protected] (V. Frisardi). 0163-7827/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.plipres.2011.06.001

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Contents 1.

2.

3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Lipids and their importance in neural membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Glycerophospholipid composition of neural membranes in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Glycerophospholipid-derived lipid mediators in brain from patients with Alzheimer’s disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Enzymic lipid mediators of arachidonic acid and docosahexaenoic acid metabolism in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Arachidonic acid and phospholipase A2 activity in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Eicosanoids, reactive oxygen species, and docosanoids in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Docosahexaenoic acid (DHA) and DHA-derived lipid mediators in Alzheimer’s disease pathology . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Lysophospholipids, lysophosphatidic acid, and platelet activating factor in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.5. Cannabinoids in Alzheimer’s disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Non-enzymic lipid mediators of arachidonic acid and docosahexaenoic acid metabolism in Alzheimer’s disease . . . . . . . . . . . . . . . . . . 2.2.1. 4-Hydroxynonenal in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Isoprostanes, neuroprostanes, isofurans, neurofurans, isoketals, and neuroketals in Alzheimer’s disease . . . . . . . . . . . . . . . . . . 2.2.3. Acrolein and malondialdehyde in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular mechanism associated with lipid mediator-mediated neurodegeneration in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction It has long been known that in several chronic diseases with genetic and lifestyle components (e.g., dietary factors), there is also a perturbed intracellular lipid metabolism. Therefore, a lipidomic approach was recently developed to better understand the lipid molecular profile not only in cardiovascular but also in neurodegenerative diseases [1]. Alzheimer’s disease (AD) is the most common form of dementia and, at present, there is still no a curative treatment for this devastating disease [2]. Actually, the lack of effective treatments is due to complexity of the pathophysiology of the disease that may have multifactorial components. Growing evidence supported the influence of lipid changes in the process of normal cognitive aging and in the etiology of age-related neurodegenerative diseases, although it remains open the question if altered brain lipids levels are cause or consequence of aging and/or AD or if there is a threshold in these changes which may result in normal or pathological conditions [3]. Dementia is not considered only a neurological disease but a scary and alarming social problem, especially if we consider the impressive proportions that it will reach in the next years especially when one considers the staggering proportions that will reach in the coming years. In fact, the 2010 estimates suggested 5.3 million of AD cases in the US [4], with >26 million patients with AD worldwide, and an expected increase to more than 106 million by 2050 [5]. From a neuropathological view, AD involves aberrant protein processing and is characterized by the presence of both intraneuronal protein clusters composed of extracellular aggregates of b-amyloid (Ab) [senile plaques (SPs)], by endoproteolytic processing of the amyloid precursor protein (APP), and paired helical filaments of hyperphosphorilated tau protein [neurofibrillary tangles (NFTs)]. Hyperphosphorylation of tau protein causes neuronal synapse dysfunction and loss of cell-cell communication, whereas disturbed Ab kinetics may be pivotal for pro-inflammatory pathways that affect cellular integrity [6]. At present, it is difficult to equivocally delineate if these pathological features of AD are causative or consequential, and the therapeutic challenge needs firstly of identifying the way-triggers that compromise cellular integrity [7]. Ab induces lipid peroxidation and its sequelae could lead to neuroapoptosis [8], but it is equally true that the altered lipid signaling could exacerbate the pathological features of disease. However, the hypothesis that Ab is the key pathologic factor affecting the disease process is strongly challenged by the finding that immunization with pre-aggregated Ab1–42 (AN1792)

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resulted in almost complete removal of the SPs from the brain of the patients but did not prevent progressive cognitive and clinical decay [9]. These negative finding have been recently echoed by the failure in two large Phase III clinical trials of semagacestat, a compound that inhibits c -secretase, the pivotal enzyme that generates Ab, although the drug showed to dramatically reduce the production of Ab in the central nervous system (CNS) of humans [10]. Indeed, Ab may have a physiological role in modulating synaptic plasticity and hippocampal neurogenesis [11]. Ab deposition may simply represent a host response to an upstream pathophysiologic process or serve a protective function likely as an antioxidant/metal chelator [11]. In neurodegenerative process, the large attention devoted to lipids has ancient origin. In fact, Alois Alzheimer first described ‘‘the extraordinarily strong accumulation of lipoid material in the ganglion cells, glia and vascular wall cells’’ in the human brain of demented patient [12]. However, only in recent years thanks to impressive progress in imaging mass spectrometry (IMS), especially matrix-assisted laser desorption and ionization (MALDI)– IMS, it was possible to visualize in tissue sections the distribution of various lipid bio-molecules [13] and their endogenous metabolites, so creating an increasingly important research area around the role of cholesterol and other lipid components into pathogenesis of cognitive disorders. In fact, the brain is the most cholesterol-rich organ in the body, containing approximately 25% of total [14] where it is unesterified and it resides in the myelin sheaths and in the plasma membranes of astrocytes and neurons. Furthermore, neural membranes are composed of glycerophospholipids (GPs), sphingolipids, and proteins asymmetrically distributed between the two leaflets of lipid bilayers. In addition to structural integrity role to neural membranes, GPs, sphingolipids, and cholesterol belong to the signal transduction network that conveys extracellular signals from the cell surface to the nucleus inducing a biological response at the gene level. This is performed by second messengers (bioactive lipid mediators) through nuclear pores (large proteinaceous assemblies) that provide the sole gateway for the exchange of material between cytoplasm and nucleus lipid mediators [15]. Levels of GPs are decreased in brain autopsy samples from AD patients compared to age-matched controls [16] accompanied by increased activities of lipolytic enzymes and elevated concentrations of phospholipid degradation metabolites [17]. This emphasizes the possibility that a specific diet, in particular the Mediterranean dietary pattern and its nutraceutical properties, could modify the progression of AD by interfering with

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the alteration of molecular pathways involved in the Ab cascade [18]. A very recent update of the GP classification was based on the 2005 ‘‘comprehensive classification system for lipids’’ developed and established by the International Lipid Classification and Nomenclature Committee under the sponsorship of the LIPID MAPS Consortium [19]. GPs are amphipathic molecules that are required not only for optimal functioning of integral membrane proteins, receptors, transporters, and ion channels, but also act as storage depot for lipid mediators [15]. The pathogenesis of AD may be linked also to alterations in neural membrane composition, and GP-derived lipid mediators-mediated oxidative stress, and neuroinflammation. However, it remains unclear how these factors result in neuronal dysfunction and cell death. The purpose of the present review article is to describe the contribution of GP-derived lipid mediators in oxidative stress and neuroinflammation to a wider audience with the hope that this discussion will initiate more studies not only on the role of GP-derived lipid mediators in normal and AD brain, but also on interplay among GP-, sphingolipid-, and cholesterol derived lipid mediators leading to neuronal cell death. For this purpose, we described the possible role of the metabolism of principal GPs and GP-derived lipid mediators in AD pathology, trying also to underline the crucial importance of diet in the prevention of late-onset AD. We searched from the English literature published before December 2010 through the PubMed database of NCBI (available at: http://www.ncbi.nlm.nih.gov) by author and the following keywords: glycerophospholipids, lipid mediators, arachidonic acid, docosahexaenoic acid, eicosanoids, docosanoids, endocannabinoids, lysophosphatidylcholine, platelet activating factor, diet, polyunsaturated fatty acids, dementia, and Alzheimer’s disease. 1.1. Lipids and their importance in neural membranes Neural membranes are composed of GPs, sphingolipids, cholesterol and proteins, which are held together by hydrophobic, coulombic, van der Wall forces, and hydrogen bonding. The distribution of lipids in two leaflets of lipid bilayer is asymmetric [20]. In

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GPs, glycerol is esterified at carbon-3 (an a-carbon) with phosphoric acid and a nitrogenous base. Carbon atom 1 contains a long chain fatty acids (palmitic or stearic acids), whereas carbon atom 2 is esterified with arachidonic acid (AA) or docosahexaenoic acid (DHA) [20,21]. The presence of GPs and sphingolipids in neural membranes strengthens the lipid asymmetry while the occurrence of cholesterol and sphingolipids leads to the formation of lipid rafts, which are platforms for signal transduction processes. In addition to lipids, neural membranes also contain transmembrane and peripheral proteins of various shapes, molecular masses, and charges. The binding of GPs to proteins is necessary not only for vertical positioning and tight integration in the lipid bilayer, but also for optimal activity of receptors, ion channels, and membrane bound-enzymes [21–23]. Neuronal activity is modulated by an interplay between membrane receptors at the cell surface and intracellular signaling proteins that are present in the cytoplasm (Fig. 1). In brain, cellular homeostasis is maintained through a complex meshwork of GP-, sphingolipid-, and cholesterol-derived lipid mediators, transporters, and enzymic pathways established among plasma membrane, subcellular organelles, cytoplasm, and nucleus [24]. This composite meshwork not only responds to environmental changes by modulating genes for enzymes associated with synthesis and degradation of lipid mediators, but also induces the synthesis of survival factors such as neurotrophins [24]. The binding of agonists with receptors results in enhancement of neural membrane GP, sphingolipid, and cholesterol metabolism through the activation of phospholipases A2 (PLA2), sphingomyelinases and cytochrome P450-dependent oxygenases, and in generation of GP-, sphingolipid-, and cholesterol-derived lipid mediators. These latter differ in structural composition and exert a diverse array of effects on cellular functional activities including neural cell homeostasis, immune responsiveness, oxidative stress, and neuroinflammation [24]. Enzymatic lipid mediators derived from the degradation of GPs include eicosanoids, lysophospholipids, platelet activating factor (PAF), endocannabinoids (ECs), and docosanoids. The nonenzymatic lipid mediators of GP metabolism are isoprostanes

Fig. 1. Intracellular lipid signaling and neuronal cell activity: roles of lipid mediators.

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(isoPs), neuroprostanes (NPs), isofurans (isoFs), neurofurans (NFs), isoketal (isoKs), neuroketals (NKs), 4-hydroxynonenal (4-HNE), and 4-hydroxyhexanal (4-HHE) [23,25–31]. Levels of GP-derived lipid mediators in neural and non-neural tissues are partly regulated by diet [32–34]. The high intake of food enriched in AA (vegetable oils) not only elevates levels of eicosanoids, but also up-regulates the expression of pro-inflammatory cytokines [34]. AA-enriched diet can also increase levels of isoPs, which have vasoconstrictive effects in pulmonary artery, coronary arteries, cerebral arterioles, retinal vessels, and portal vein [35]. Thus, AA and its metabolites (eicosanoids) produce prothrombotic, proaggregatory, and pro-inflammatory effects [34]. In contrast, diet enriched in DHA (fish and fish oil) protects neuronal and brain functions (synaptic function and memory capacities) by docosanoids [35], which not only down-regulate pro-inflammatory cytokines, but also have anti-inflammatory, anti-thrombotic, antiarrhythmic, vasodilatory, and anti-exitotoxic effects [32,34,36– 38]. This suggests that dietary AA/DHA ratio could be crucial for designing nutrition-based strategies able to prevent AD as well as other lipid- and age-related diseases whose prevalence is progressing in older populations [39]. 1.2. Glycerophospholipid composition of neural membranes in Alzheimer’s disease Although the molecular mechanism associated with the AD pathogenesis remains largely unknown, it is proposed that receptormediated alterations in membrane composition and integrity along with neuroinflammation and oxidative stress may be closely related to the AD pathogenesis [40]. Studies on GP composition indicate that levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI) are significantly decreased in neural membranes from different regions of AD patients compared to age matched control human brain [41–47] (Table 1). This decrease in phospholipids may be due to the stimulation of various isoforms of PLA2 including PE–PLA2, cytosolic PLA2 (cPLA2), and secretory PLA2 (sPLA2) [23,48–50]. Physicochemical and pathological consequences of activation of PLA2 isoforms and enrichment in GP metabolism include not only changes in membrane fluidity and permeability, but also alterations in ion homeostasis leading to oxidative stress. Many of the GP degradation products are proinflammatory and their generation in the brain is accompanied by the activation of astrocytes and microglia and the release of inflammatory cytokines. These cytokines in turn propagate and intensify oxidative stress and neuroinflammation by a number of mechanisms including further up-regulation of sPLA2 isoforms, cyclooxygenase (COX), and nitric oxide synthases (NOS) [23,48–50]. Although the cause of increased activities of PLA2 isoforms in AD brain is not fully understood, there are several possibilities.

Table 1 Levels of glycerophospholipid-derived lipid mediators in Alzheimer’s disease patients. Lipid mediator

Levels

References

Eicosanoids Lysophosphatidylcholine Cannabinoids 4-Hydroxynonenal 4-Hydroxyhexanal Isoprostane Neuroprostane Isoketal Neuroketal Isofuran Neurofuran Malondialdehyde Acrolein

Increased Decreased Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased

[104,105] [17] [206] [216] [221] [235,236] [232] Not determined in humans Not determined in humans [254] [255] [260] [261]

Firstly, accumulated Ab may increase cPLA2 activity [51,52] which is blocked by cPLA2 antisense oligonucleotides [53]. The second possibility is that the activation of astrocytes and microglia in AD may result in expression of the cytokines, tumor necrosis factora (TNF-a), interleukin(IL)-1b, and IL-6, that have been known to stimulate cPLA2 activity [54]. Another mechanism of cPLA2 activation may involve the proteolytic cleavage of cPLA2 by caspase-3 [55] and this activation is retarded by a specific tetrapeptide inhibitor (acetyl-Asp-Glu-Val-Asp-aldehyde) of caspase-3. Finally, metabolites of sphingolipid metabolism (ceramide and ceramide 1 phosphate), which accumulate in AD brain, also stimulate cPLA2 [56–60]. Among PLA2 isoforms, Ca2+-independent PE–PLA2 initiates the neural injury probably by decreasing levels of plasmalogens resulting in increased neural membrane permeability and Ca2+ influx. This Ca2+ influx facilitates the translocation of cPLA2 from cytosol to plasma membrane as well as nuclear membranes, where its activation leads to the hydrolysis of neural membrane PC. As concentration of Ca2+ reaches in mM, the sPLA2 may be activated promoting neural cell injury and death. Thus, in injury process sequence, PE–PLA2 is situated at the proximal end, cPLA2 in the middle, and sPLA2 at the distal end [40,61]. Activation of cPLA2 and PE–PLA2 generates AA and DHA, respectively. These fatty acids are metabolized to lipid mediators, which not only play important roles in internal and external communications, but also modulate cellular responses such as growth, differentiation, adhesion, migration, and apoptosis [23,25–31] (Fig. 1). Increase in levels of lipid mediators may contribute both to abnormal signal transduction processes and to neurodegeneration in AD. 2. Glycerophospholipid-derived lipid mediators in brain from patients with Alzheimer’s disease It is well known that GPs are not only components of neural membranes, but also precursors for lipid mediators. Proportions of AA and DHA vary considerably in various classes of GPs in different regions of brain. AA is distributed rather evenly in gray and white matter and among the different cell types in the brain, whereas DHA is highly concentrated in synaptic membranes. In neural plasma and synaptic membranes, GP homeostasis is based on a balance between GP hydrolysis by various phospholipases and resynthesis of GPs by the reacylation/deacylation cycle and de novo synthesis. 2.1. Enzymic lipid mediators of arachidonic acid and docosahexaenoic acid metabolism in Alzheimer’s disease Hydrolysis of GPs by PLA2 results in generation of AA or DHA and lysophospholipids. AA is metabolized by cyclooxygenases (COX-1 and COX-2), lipoxygenases (LOX), and epoxygenases (EPOX) into prostaglandins (PGs), leukotrienes (LTs), lipoxins (LXs), and thromboxanes (TXs), as well as hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatetraenoic acids, and dihydroxyeicosatrienoic acids [62,63]. These metabolites are collectively called as eicosanoids. Some PGs and LTs produce pro-inflammatory effects while others induce anti-inflammatory actions [30]. Among AA-derived lipid mediators, LXs produce potent anti-inflammatory effects. DHA is metabolized by 15-LOX into resolvins (Rvs) and neuroprotectins (NPs) and the action of 14-LOX on DHA generates maresins (MaRs) [64–66]. These metabolites are called as docosanoids. Lysophospholipids, the other product of PLA2-catalyzed reaction, are subjected to both CoA-dependent and CoA-independent acylation for restoring GP contents of neural membranes or acetylated by acetyl-CoA in PAF, a potent pro-inflammatory active lipid mediator involved in intracellular and extracellular communication

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[67]. Lysophospholipids are also hydrolyzed by lysophospholipases into fatty acids and glicerophosphodiesters. 2.1.1. Arachidonic acid and phospholipase A2 activity in Alzheimer’s disease AA is an n-6 polyunsaturated fatty acid (PUFA) that must be introduced with the diet or synthesised from its precursor linoleic acid (LA) in the liver. The brain contains relatively low levels of LA, and very little LA is converted into AA within the brain [68]. Thus, the brain relies on a steady supply of AA from the plasma. Although several lipid pools, including plasma lipoproteins and lysophospholipids, may contribute to brain AA levels, their quantitative contribution remains unclear [69,70]. Plasma unesterified AA enters the brain at a rate of 2–5 pmol/s per g of brain in rodents and 17.8 mg/day per whole brain in adult humans [71]. Upon its entry into the brain, AA is activated by a long-chain fatty acylCoA synthetase (LC-FACS) (Fig. 2) and can be esterified into the sn-2 position of neural phospholipids. PLA2s constitute a superfamily of enzymes and they are activated via coupling to serotonergic (5-hydroxytryptaminergic) [72], glutamatergic [73], dopaminergic [74], and cholinergic [75] receptors. In general, cPLA2, which is located at postsynaptic terminals, is thought to be selective for releasing AA from the sn-2 position of neural phospholipids [76]. After its release by PLA2, AA is transported to the endoplasmic reticulum (ER) and cycled back into phospholipids by the serial actions of LC-FACS and acyltransferase. However, a small fraction is metabolized to eicosanoids and other products or undergone beta-oxidation after being transferred to mitochondria from the arachidonoyl-CoA pool by carnitine palmitoyl transferase [77].

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AA intervenes in regulating the activity of many enzyme proteins including protein kinase A and C (PKC), NADPH oxidase, choline acetyltransferase, and caspase 3 [78]. Recently, Niu and colleagues explored the expression of the apoptosis-related proteins caspase-3 and nuclear factor-kappa B (NF-kB) in the hippocampus of Tg2576 mice (transgenic mice expressing comparable levels of mutant human APP). They found that both neuronal apoptosis and NF-kB activity decreased gradually with increasing age in wild type while the number of caspase-3-positive or NF-kBpositive pyramidal cells in Tg2576 mice was greater than that in age-matched wild type mice, highlighting the role of NF-kB and caspase 3 in hippocampal neuroapoptosis [79]. Furthermore, AA intervenes in ion channels modulation and neurotransmitter release especially acting on cholinergic and glutamatergic receptor [80], on induction of long term potentiation (LTP), and neural cell differentiation. Finally, it modulates gene expression interacting with several elements of gene structure [15]. There is a large body of evidence for the involvement of glutamate receptors in LTP, neuronal plasticity, learning, and memory [81,82], processes where products of PLA2 may modulate glutamate release, postsynaptic receptor activation, and presynaptic responses [83]. AA released by PLA2 has the potential to significantly affect glutamate excitotoxicity. In fact, the activities of cPLA2 and sPLA2 increases upon exposure of cortical neurons to glutamate [83], supporting the functional link between PLA2 activity and stimulation of glutamate receptors. This link was confirmed also by studies where the application of a cPLA2a inhibitor to cultured hippocampus significantly protected the pyramidal neurons from oxygen–glucose deprivation [84], as well as reduced the release

Fig. 2. Principal targets of arachidonic acid (AA) and docosahexaenoic acid (DHA) enzymatic metabolism in neurodegenerative/neuroprotection pathways. Ab, b-amyloid; BACE1, b -site APP cleavage enzyme; BAD, BCL-2-associated death promoter; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2; COX, cyclooxygenase; EP1, prostaglandin receptor 1; GP, glycerophospholipid; GSK-3, glycogen synthase kinase 3; IL-b, interleukin-b; LC-FACS, long-chain fatty acyl-CoA synthetase; MAPK, mitogenactivated protein kinase; NF-kB, nuclear factor-kappa B; NO, nitric oxide; NPD1, neuroprotectin D1; PK, protein kinase; PL, phospholipase; PLA2, phospholipase A2; PG, prostaglandin; PPAR-c, peroxisome proliferator-activated receptor-c; RvD1, resolvin D1; TLR, toll-like receptors; TNF-a, tumor necrosis factor-a; REC, receptor; ROS, reactive oxygen species; sAPP, soluble amyloid precursor protein.

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of excitatory amino acids from the cortical surface after vessel occlusion in the rat [85]. sPLA2 showed a synergistic effect on the transient increase of Ca2+ in hippocampal neurons and the release of AA in primary cortical neurons induced by non-toxic and toxic glutamate concentrations [83]. In primary cortical neurons, the combination of exogenous sPLA2 and glutamate also potentiates the release of AA from PC and PE [83]. However, the exact contribution of different phospholipases (especially PLA2 isoforms) to specific mechanisms of glutamate-mediated synaptic transmission remains to be further elucidated. Using a novel fluorogenic method to assess changes in PLA2 activity by flow cytometry, Chiricozzi and colleagues showed that the group IIA sPLA2 isoform is specifically activated in cortical neurons following stimulation of N-methyl-D-aspartate glutamate receptor subtype (NMDAR), requiring for its activation, Ca2+ and reactive oxygen/nitrogen species, while inhibition of its activity fully preventes NMDAR-mediated neuronal apoptotic death [86]. In cultured neurons, AA amplifies the calcium response to N-methyl-D-aspartate (NMDA) stimulation [83]. In addition to oxidative stress and Ca2+ increase stimuli, the PLA2 activity is accentuated during an acute neuronal injury [87]. Alexandrov and colleagues identified a hypoxia-sensitive domain in the 50 -untranslated region of the human PLA2 gene that induces PLA2 mRNA in brain microvascular endothelial cells [88] (Fig. 2). Moreover, it is possible to hypothesize a ‘‘short-circuit’’ in this lipid framework where the ischemic injury and reperfusion activate cPLA2, resulting in an excessive release of AA, amplifying the processes of excitotoxicity and so on. The interaction between PLA2 and the mitogen-activated protein kinase (MAPK) pathways has potential importance in brain after ischemic and reperfusion injury. Some authors demonstrated that cPLA2 enhances reactive oxygen species (ROS) formation by middle cerebral artery occlusion, while others have shown that oxidative stress in mouse embryonic stem cells causes MAPK dependent phosphorylation of cPLA2 [87]. This interaction has the potential to form a positive feedback loop in which PLA2dependent ROS increases kinase activation which leads to further cPLA2a activation. Alessandrini and colleagues showed that in vivo cerebral ischemic and reperfusion injury activates these kinases and that inhibition of MAPK/extracellular signal-regulated kinase (ERK) kinase is neuroprotective [89]. Oxidative stress activates p38 and MAPK in neurons, which then activate caspases 8 and 9, leading to neuronal apoptosis. Thus, the interaction of cPLA2 with p38/MAPK may amplify ischemic injury. In fact, the inhibition of p38 activity in the rat decreases phosphorylation of cPLA2 and attenuates stroke injury [87] (Fig. 2). It is also possible that AA released by PLA2 may directly stimulate phosphorylation of p38/ MAPK and ERK1/2 [90]. When the PLA2 is stimulated by exogenous causes, the AA amount increases producing a variety of detrimental effects on neuronal cell structure and function, causing intracellular acidosis and uncoupling oxidative phosphorylation, with mitochondrial dysfunction, a modified membrane permeability, NF-kB activation, and decreased neuronal viability [78]. A pilot study using transcranial doppler demonstrated an altered cerebral hemodynamics in early AD where the distinct pattern of altered cerebral hemodynamics including a reduced cerebral blood flow velocity, and increased cerebral vascular resistance not fully explained by brain atrophy [91]. Another study examined the regional cerebral blood flow (rCBF) in incident mild cognitive impairment (MCI) and AD by using continuous arterial spin-labeling magnetic resonance imaging suggesting that the transition from normal cognition to AD may be associated with dynamic pathological processes in the brain, and this is reflected by both decreased and increased rCBF [92]. Both MCI and AD patients had decreased rCBF in the posterior cingulate gyrus with extension to the medial precuneus compared with that in control subjects.

Moreover, while MCI patients had increased rCBF in the left hippocampus, right amygdala, and rostral head of the right caudate nucleus and ventral putamen and globus pallidus compared with that in control subjects, AD patients had decreased rCBF in the left inferior parietal left lateral frontal, left superior temporal, and left orbitofrontal cortices relative to that in control subjects and MCI patients. AD patients also had increased rCBF in the right anterior cingulate gyrus compared with that in control subjects [92]. In according to this vascular pattern in AD patients, a decrease in PLA2 activity was found in the parietal and temporal cortex, as well as the prefrontal cortex of the AD brain, suggesting a more closed link between phospholipid metabolism and altered blood regulation in AD [84]. On the other hand, immunohistochemical studies showed an increase in cPLA2 immunoreactivity associated with the glial fibrillary acidic protein-positive astrocytes in the AD brain [93]. In a recent gene array study, profiling of 12,633 genes in the hippocampal cornu ammonius 1 (CA1) area of AD patients indicated an increase in cPLA2 and COX-2 expression, as well as an up-regulation of several apoptotic and pro-inflammatory genes [94]. Moreover, cPLA2 has been invoked to mediate ischemic injury in the hippocampus especially at hippocampal CA1 subfield, wellknown to be highly vulnerable to ischemia [84]. These observations are not contradictory if we consider the eclectic nature of PLA2 that is similar to a key that may open several pathways depending on a particular stimulus or a specific cell membrane. 2.1.2. Eicosanoids, reactive oxygen species, and docosanoids in Alzheimer’s disease As stated above, enzymatic oxidation of AA results in generation of PGs, LTs, and TXs, which produce a wide range of biological actions including potent effects on inflammation, vasodilation, vasoconstriction, apoptosis, and immune responses. Because of their amphiphilic nature, PGs, LTs, and TXs can cross cell membranes and act on their receptors on the neighboring cells. PGs mediate their signaling through four distinct G protein-coupled receptors (EP1, EP2, EP3, and EP4), which are encoded by different genes and are differentially expressed on neuronal and glial cells throughout the brain [30]. These receptors display different actions as for example Ca2+dependent neurotoxicity in ischemic injury mediated by EP1 activation or microglial-induced paracrine neurotoxicity and microglia internalization suppression of aggregated neurotoxic peptides by EP2 activation [95]. It is very interesting to understand the articulated and regulatory cross-talk between several receptors and enzymes involved in different pathways. In fact, for example the NMDAR regulates COX-2 neuronal expression, which provides a mechanistic link between PG signaling and excitatory neurotransmission [96]. Inhibition of COX-2 activity early after glutamate exposure suppresses NMDA-mediated neuronal excitotoxicity [97–99] and the EP1 receptor antagonist SC51089 reduces NMDA mediated neurotoxicity in mice, indicating that EP1 is a downstream excitotoxic effector [100]. Furthermore, EP1 enhances neuronal Ca2+ dysregulation induced by NMDAR activation through impairment of Na+–Ca2+ exchange in vitro. Conversely, EP2 and EP4 demonstrate a neuroprotective effect during excitotoxic conditions. Organotypic culture preparations from rat hippocampus or spinal cord show neuroprotection in excitotoxic conditions when treated with the EP2 agonist butaprost [101] or the EP4 agonist ONO-AE1-329 [102]. These encouraging results on animal models may support the potential efficacy of targeting specific EP receptor subtypes in AD, especially for EP2. In addition to generating eicosanoids, COX, LOX, and EPOXcatalyzed reactions also produce ROS, which include both oxygen free radicals (superoxide radicals, hydroxyl, and alkoxyl radicals) and peroxides (hydrogen peroxide and lipid hydroperoxide). Although brain has multiple potential sources of ROS generation

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and a large oxidative capacity, its ability to counteract the production of ROS is very limited [23]. At low levels, ROS function as signaling intermediates in the regulation of fundamental cell activities such as growth and adaptation responses. At higher concentration, ROS contribute to oxidative stress. The biological targets of ROS include membrane proteins, unsaturated lipids, and DNA [103]. The reaction between ROS and proteins or unsaturated lipids in the plasma membrane leads to a chemical cross-linking of membrane proteins and lipids and a reduction in membrane unsaturation. The depletion of unsaturation in membrane lipids not only decreases membrane fluidity, but also results in the inhibition of membrane-bound enzymes, ion-channels, and receptors [24]. A significant increase in COX-1 and COX-2 expression, immunoreactivity, and levels of PGs is observed in cerebral cortex and hippocampal regions of AD brains compared to age-matched normal human brain [104,105]. This increase in COX-1 and COX-2 expression and immunoreactivity correlates with the number of SPs, neuronal atrophy, and increase in levels of PGE2 found in AD [104–109] (Table 1). COX-1 is primarily expressed in microglia, which are associated with fibrillar Ab deposits. It is suggested that in AD brain COX-1 and COX-2 are associated with inflammatory and regenerating pathways, respectively [109]. In addition, COX-2 expression is also involved in the regulation of cell cycle activity, and cell cycle abnormalities are associated with the pathogenesis of AD. Re-entry into the cell cycle may underlie COX-2-mediated neuronal damage in AD [110]. Like COX-1 and COX-2, the expression of 5-LOX is also upregulated in AD hippocampus, where it is primarily associated with neurofibrillary structures and SPs. Furthermore, Ab peptide fibril-

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ization and tau hyperphosphorylation themselves stimulate LOX activity, creating a vicious cycle of pathological cascades, neuroinflammation and oxidative stress that may perpetuate neuronal degeneration and loss of synapses in AD [107]. At present, no information is available on EPOX activity and expression in AD brain. In vitro studies indicate that LOX inhibitors, nordihydroguaiaretic acid, AA861, and baicalein, and the EPOX inhibitors, SKF25A and metyrapone prevent cell death in neuronal cultures, suggesting that LOX and EPOX pathways may also be involved in neurodegeneration [111]. Eicosanoid-mediated neuroinflammation may be an important component of AD pathophysiology [112]. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, ROS, and inflammatory enzyme systems that are expressed and released by microglia, astrocytes and neurons, facilitating neuroinflammation in the AD brain [113]. Although neuroinflammation promotes neurodegeneration in AD, recent data indicate that inflammatory mediators may stimulate APP processing by up-regulation of b-site APP cleavage enzyme (BACE1) and therefore are able to establish a vicious cycle [113] (Fig. 3). Compelling epidemiologic studies have repeatedly shown that protracted use of non-steroidal anti-inflammatory drug (NSAID) inhibitors of COX isoforms prior to the onset of dementia can substantially lower the risk of subsequently developing dementia (50% or more), especially in subjects carrying one or more e4 allele of the apolipoprotein E (APOE) [114,115]. Unfortunately, the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT), a large clinical trial conducted in 2528 cognitively normal individuals at risk

Fig. 3. Principal molecular mechanism associated with lipid mediator-mediated neurodegeneration. AA, arachidonic acid; Ab, b-amyloid; ADAM, A Disintegrin And Metalloprotease; sAPPa, soluble amyloid precursor protein a; sAPPb, soluble amyloid precursor protein b; APP, amyloid precursor protein; BACE1, b-site APP cleavage enzyme; CERase, ceramidase; 4-HNE, 4-hydroxynonenals; IsoP, isoprostane; COX-2, cyclooxygenase 2; cPLA2, cytosolic phospholipase A2; DHA, docosahexaenoic acid; 15LOX, lipoxygenases; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; NMDAR, N-methyl-D-aspartate glutamate receptor subtype; PC, phosphatidylcholine; PE, phosphatidylethanolamine; ROS, reactive oxygen species; p75-NTR, p75 neurotrophin receptor; SM, sphingomyelin; SMase, sphingomyelin phosphodiesterase; Sph, sphingosine; SphK, sphingosine Kinase; Sph-1P, shingosine 1 phosphate.

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for AD (age > 70 years and first degree relative with dementia) aimed at testing this association with both a non-selective (naproxen) and COX2-selective (celecoxib) NSAID, was terminated early because of increased ‘‘thrombotic events’’ (myocardial infarct and ischemic stroke) in individuals randomized to drug [116]. Analyses that excluded the seven individuals with dementia that were erroneously enrolled in the study, showed increased hazard ratios for AD compared to placebo with both celecoxib and naproxen [117]. Masked long-term follow-up of the enrolled subjects is ongoing. A recent analyses of the 4-year follow-up data surprisingly revealed that subjects previously exposed to naproxen were protected from the onset of AD by 67% compared to placebo [118]. The overall results of the ADAPT trial suggest that people who had disease process ongoing in their brain (even if asymptomatic) at the beginning of the trial indeed worsened if they took NSAIDs, which accelerated their underlying disease. In contrast, people who had brain completely normal at baseline and took naproxen for 1–3 years appeared to fare better. At the long-term examination, they had a lower incidence of AD than did those on placebo [115]. Therefore, while there is an ongoing debate over the risks associated with protracted use of NSAIDs in the elderly, clinical research has turned its attention to individual PG receptors, rather than to suppression of the whole PG pathway by NSAIDs, so maintaining the therapeutic efficacy, limiting toxicity. It is believed that a better understanding of the PGE2 receptor EP subtypes may help to clarify the relation between inflammation and AD, and to develop novel therapeutic strategies targeting specific EP receptors for AD treatment [119,120]. In transgenic mouse models of familial AD, in which was observed age-dependent accumulation of Ab along with significant microglial activation, has been noted that NSAID treatment could reduce Ab peptide deposition and reverse mild behavioral deficits [121]. COX inhibition in the PG pathway is the likely mechanism by which NSAIDs suppress Ab deposition in aged transgenic mouse brain. A recently proposed alternative hypothesis based on cell culture studies suggests that high, supraphysiologic concentrations of some NSAIDs can alter c-secretase (an APP cleaving enzyme) activity and reduce the ratio of the most toxic Ab peptide species (Ab1–42) [122]. However, in vivo pharmacological dosing of these NSAIDs challenges this alternative hypothesis [123]. At present, it is not clear what happens first in vivo, if formation of toxic aggregated Ab species or neuronal oxidative damage because there is evidence that neuronal oxidative damage is secondary to Ab deposition, and viceversa [124]. There are several studies showing that aggregated Ab peptides are directly neurotoxic to primary neuronal cell cultures [125,126]. Treating mouse primary cerebral cortical neurons with the EP2 agonist butaprost or the EP3/EP4 agonist 1-hydroxy-PGE1 suppresses aggregated Ab peptide mediated neurotoxicity [126]. At the end, a cycle between the production of oxidative damage and formation of neurotoxic Ab deposition it is the likely underlying mechanism. Furthermore, Ab acts through a biphasic neurotoxic mechanism that is conformationdependent. Aside from its ability to generate oxidative stress, Ab also leads to activation of some redox-sensitive transcription factors, such as NF-jB, ERK, c-Jun N-terminal kinase (JNK), and p38/ MAPK pathways [18]. Some of these, in turn, lead to tau protein hyperphosphorylation. 2.1.3. Docosahexaenoic acid (DHA) and DHA-derived lipid mediators in Alzheimer’s disease pathology Both prospective and cross-sectional studies suggested that consumption of n-3 PUFAs may lower the AD risk, and in mouse models DHA modified the expression of AD-like brain pathology [127]. Like AA, DHA is oxidized by 12/15-LOXs. This results in the generation of Rvs, NPs, and MaRs. From eicosapentaenoic acid (EPA) come Rvs of the E series (RvE1) that carry potent biological actions (i.e., 1–10 nM

range), while from DHA come Rvs of the D series (RvD1) that interact with their respective receptors. The complete stereochemistry of RvD1 (7S,8R,17S,-trihydroxy-4Z,9E,11E,13Z,15E,9Z-docosahexaenoic acid) has been described in detail [29,128]. Similar in structure to eicosanoids but less potent or devoid of bioactions, the Rvs, docosatrienes, and NPs evoke potent biological actions in vitro and in vivo. Rvs (resolution-phase interaction products and docosatrienes antagonize the effects of AA-derived PGs, LTs, and TXs, and display potent anti-inflammatory and immunoregulatory properties [129]. With microglial cells that liberate cytokines in the brain, the Rvs block TNFa-induced IL-1b transcripts and are potent regulators of leukocyte infiltration of the brain [130]. Of the docosatriene-derived family, the NPD1 pathway acts as a potent regulator of leukocytes influx in exudates at site where it is formed from endogenous precursors and limits stroke brain injury and retinal pigmented cellular damage [131]. Although, the occurrence of receptors for Rvs has been proposed, these receptors have not been characterized from neural and non-neural tissues. Like Rvs, NPD1 produces anti-inflammatory and anti-apoptotic effects. It retards the infiltration of polymorphonuclear neutrophils (PMN) [131], down-regulates the expression of cytokines in the glial cells [130,131], and produces neuroprotective effects in the ischemic injury [65]. The NPD1 generation represents an endogenous neuroprotective mechanism that promotes neural cell survival not only via its anti-inflammatory effects, but also by the induction of anti-apoptotic and neuroprotective gene-expression programs that suppress Fb1–42-mediated neurotoxicity in AD [132–134] (Fig. 3). Recent studies on DHA and NPD1 metabolism in control and aged 3  Tg-AD mouse hippocampus and aging human neuronal-glial primary cells indicate that NPD1 not only down-regulates Ab1–42induced expression of the pro-inflammatory enzyme COX-2 and of B-94 (a TNF-a-inducible pro-inflammatory element), but also suppresses Ab1–42 peptide. In fact, DHA metabolism downregulates the expression of BACE1, while actives a-secretase [A Disintegrin And Metalloprotease (ADAM)10] and up-regulates the neuroprotective sAPPa, thus shifting the cleavage of APP holoenzyme from the amyloidogenic to the non-amyloidogenic pathway [135] (Fig. 3). Elucidation of the molecular mechanisms through NPD1 and other DHA metabolites enhance neuronal health is important for understanding how decreased levels of these important signaling molecules may contribute to the pathogenesis of AD and other neurodegenerative diseases. The formation of NPD1 from DHA is tightly regulated by the redox state of neurons. Increased oxidative stress caused by Ab exposure, hypoxia, and IL-1b activity upregulates PLA2 generating NPD1, which exerts a powerful negative feedback mechanism to control excessive oxidative stress [136]. In addition, the actions of DHA and NPD1 include up-regulation of the B-cell lymphoma 2 (BCL-2) family of anti-apoptotic proteins, down-regulation of pro-apoptotic signaling pathways, and inhibition of the pro-inflammatory, COX-mediated, production of eicosanoids, including prostaglandin synthesis from AA [136] (Fig. 2). Animal studies about the effects of short-term (3 months) DHA enriched diet on SP deposition and synaptic defects in forebrain of young transgenic and non-transgenic mice revealed a significant increase in DHA concomitant with a decrease of AA in both brain and liver in mice fed. SP load was significantly reduced in the cortex, ventral hippocampus and striatum of female transgenic mice on DHA diet compared to female transgenic mice on control diet. Immunoblot quantitation of the APOE receptor, LR11, which is involved in APP trafficking and Ab production, were unchanged in mice on DHA or control diets. Moreover, drebrin levels were significantly increased in the hippocampus of transgenic mice on the DHA diet [137]. In addition to memory formation, excitable membrane function, photoreceptor cell biogenesis and function, and neuronal signaling,

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DHA is required for retinal pigment epithelium (RPE) cell functional integrity. Although the entorhinal cortex and hippocampal complex are best known as the sites of early AD pathology, increasing evidence shows that the eye, particularly the retina, is also affected. The AD-related changes in the retina are associated with degeneration and loss of neurons, reduction of the retinal nerve fibers, increase in optic disk cupping, retinal vascular tortuosity and thinning, and visual functional impairment [138]. In oxidative stress-challenged human RPE cells and rat brain undergoing ischemia-reperfusion, NPD1 synthesis evolves. In addition, calcium ionophore A23187, IL-1b, or the supply of DHA enhances NPD1 synthesis. A time-dependent release of endogenous free DHA followed by NPD1 formation occurs, suggesting that PLA2 releases the lipid mediator precursor. When NPD1 is infused during ischemia-reperfusion or added to RPE cells during oxidative stress, apoptotic DNA damage is down-regulated. NPD1 also up-regulates the anti-apoptotic BCL-2 proteins (BCL-2 and BCLxL) and decreases pro-apoptotic BCL-2–associated X protein (BAX) and BCL-2-associated death promoter (BAD) (Fig. 2). Moreover, NPD1 inhibits oxidative stress-induced caspase-3 activation. NPD1 also inhibits IL-1b-stimulated expression of COX-2. Overall, NPD1 protects cells from oxidative stress-induced apoptosis. Moreover, three probable mechanisms have been proposed for the visual impairment in AD: (1) the broad-band pathway deficit; (2) glaucoma; and (3) the relative dysfunction of the ventral and dorsal streams of vision [139]. Especially for the first, histological, electroretinogram, and imaging studies confirmed the loss of retinal ganglion cells in AD and understanding of how lipid signals could contribute to retinal cell survival may lead to the development of new therapeutic strategies. In macrophages, 14-LOX converts DHA into a bioactive mediator called maresin 1 (7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Zhexaenoic acid, MaR1). Action of 12-LOX on DHA transforms it into 14-hydroperoxydocosahexaenoic acid (14S-HDHA). This is followed by either reduction to 14S-HDHA and/or, via double dioxygenation (e.g., sequential 12-LOX–5-LOX) generation of 7S,14S-diHDHA. The bioactive 7,14S-diHDHA is then enzymatically converted to the potent bioactive MaR1 [66]. It acts as a specialized mediator to dampen inflammation actively, affords tissue protection, stimulates host defense, and activates resolution [66] by limiting PMN entry and stimulating macrophage uptake of apoptotic PMNs and/or zymosan. The occurrence of MaR1 and its receptors in normal and AD brain has not yet been described. In addition to specific functions in the brain, DHA has several non-specific properties which could also potentially contribute to its protective effect against the neurodegenerative process in AD. Firstly, it intervenes in giving more flexibility to neuronal membranes and it impacts on speed of signal transduction, neurotransmission, and formation of lipid rafts [127]. These latter serve as platforms for intracellular cell signaling by promoting proteinprotein and protein-lipid interactions and there is increasing evidence that they may be targets of neurodegenerative diseases, such as AD. In particular, Martin and colleagues by purifying lipid rafts of human frontal brain cortex from normal and AD patients and characterizing their biochemical lipid composition, have revealed that lipid rafts from AD brains display abnormally low levels of n-3 long chain PUFA, mainly DHA, and monoenes (mainly 18:1n-9, oleic acid), as well as reduced unsaturation and peroxidability indexes [140]. Furthermore, DHA also seems to intervene in modulating gene expression through interaction with at least four families of transcription factors – peroxisome proliferator-activated receptors (PPAR), liver retinoid X receptors, hepatic nuclear factor-4a, and sterol regulatory-element-binding protein. In particular PPARs are ligand-inducible transcriptional factors with a central role in gene expression especially by inhibiting inflammatory gene

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expression in brain cells [1]. PUFA bind PPARs with a higher affinity than saturated or monounsaturated fatty acids and induce gene transcription [127]. Moreover, using PPARc agonist and antagonist GW9662, it is shown that NPD1 also interacts with PPARc receptors and the release of Ab1–42 peptide is PPARc-dependent. Therefore, DHA plays direct and indirect protective actions against AD pathology because it increases the antioxidant and antinflammatory activity in the brain and in the other hand, counteracts the Ab1–42 peptide load in the brain. Other nuclear receptors, namely endogenous retinoic acid receptor (RAR) and retinoid X receptor (RXR), which is highly expressed in the hippocampus, could be relevant to understanding the role of DHA in AD. In fact, several studies show that DHA can specifically bind to and directly activate RXR, leading to the regulation of the expression of genes usually under the control of retinoic acid [141–143]. These results are potentially important for the treatment or prevention of AD since the retinoic acid signaling pathway is involved in the maintenance of synaptic plasticity and memory in aged animals [144–147]. Indeed, a link between the metabolism of retinoids and late-onset AD was recently proposed [148,149].

2.1.4. Lysophospholipids, lysophosphatidic acid, and platelet activating factor in Alzheimer’s disease Lysophospholipids are metabolites of GP metabolism. Neural membrane lysophospholipids include lysophosphatidylcholines (LPCs), lysophosphatidylethanolamines (LPEs), lysophosphatidylserines (LPSs), lysophosphatidylinositols (LPIs), lysoplasmalogens (lysoplasmenylethanolamine and lysoplasmenylcholine), and lysophosphatidic acid (LPA) [23]. These metabolites are transiently generated during the remodeling of GPs [150]. At high concentrations, lysophospholipids alter membrane permeability, and disturb osmotic equilibrium. Lysophospholipids interact with neural membranes lipid and enzyme components and modulate activities of membrane associated enzymes and growth factors [31]. Intracerebroventricular injections of LPC result in increase behavioral responses and allodynia in carrageenan-induced acute and chronic models of inflammatory pain [151], suggesting that generation of LPC may be closely associated with the modulation of nociceptive processes in neurons [152]. The administration of PLA2 inhibitors blocks behavioral responses and allodynia [153]. LPC induces the transformation of ramified resting microglia consisting of a small cell body and long processes with secondary branching into the activated deramified and amoeboid microglia, which actively participate in the maintenance of brain immune function [154,155]. The molecular mechanism of deramification of microglial cells remains unknown. However, LPC is known to promote microglial activation through the modulation of P2X7R signaling [156]. The deramification of microglial cells can be blocked by inhibition of non-selective cation channels and K+-Cl cotransporters. The activated microglial cells migrate to area of brain tissue, where SPs and NFT are accumulating and they engulf and destroy cellular debris [157]. Determination of LPC in cerebrospinal fluid (CSF) of AD patients and subjects with subjective memory complaints without dementia by tandem mass spectrometry indicate that LPC levels and the LPC/PC ratio are significantly decreased in CSF of AD patients compared to controls [17]. The decrease in LPC levels may be due to increase in lysophospholipase activity in AD patients [158]. The lower LPC/PC ratio in CSF of patients with AD indicates that alterations in the metabolism of choline-containing phospholipids in the brain in AD may be closely associated with membrane alterations in AD [17]. Physicochemical and pathological consequences of decrease in LPC/PC ratio may cause alterations in membrane fluidity and permeability, alterations in ion homeostasis, and induction of oxidative stress [23].

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In neural cells, LPA produces neurochemical effects, including stimulation of the release of noradrenaline from cerebral cortical synaptosomes, inhibition of glutamate uptake by astrocytes, elevation of neuronal intracellular calcium, and stimulation of dopamine release from PC12 cells [159–164]. LPA treatment induces growth cone collapse and neurite retraction in PC12 neuroblastoma cells, and primary neuronal cell cultures. LPA also induces the reversal of stellation in astrocytes [165]. In brain, LPA modulates tight-junction permeability of brain-derived endothelial cells and its high concentration disrupts blood–brain barrier (BBB) function [166,167]. It increases the migration of murine microglial cells through the activation of Ca2+-activated K+ currents [168]. Collective evidence indicates that LPA may act as an intracellular messenger in a paracrine/autocrine manner [169]. It modulates the above neurochemical responses through six types of 7-transmembrane G-protein-coupled receptors called LPA receptors. These receptors have an apparent mol mass of 38– 40 kDa. LPA receptors are classified into at least six groups namely LPA1, LPA2, LPA3, LPA4, LPA5, and LPA6 [170–172]. At present, nothing is known about changes in LPA levels in AD brain. Based on the effect of kinase inhibitors, involvement of glycogen synthase kinase-3 (GSK-3) has been proposed in phosphorylation of tau protein. Phosphorylation of GSK-3 at Ser9 inactivates GSK-3 in the majority of neurons with NFTs and dystrophic neurites of SPs in AD, and in Pick bodies. Although detailed investigations have not been performed, LPA-mediated activation of GSK-3 occurs in the Rho pathway and may represent an important link between microtubule and microfilament dynamics in AD [173,174]. PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) belongs to a family of biologically active and structurally related alkyl phospholipids synthesised by neural and non-neural cells including macrophages, platelets, endothelial cells, mast cells, and neutrophils. In brain, PAF and its receptors are involved in neural cell migration, gene expression, calcium mobilization, nociception, and LTP. PAF also modulates neural plasticity [175]. PAF synthesizing enzymes (PLA2 and acetyltransferase) are modulated by MAP kinase signaling pathways [176], whereas PAF hydrolyzing enzyme (PAF-acetyl hydrolase) is regulated by pro-inflammatory cytokines such as TNF-a, IL-1, IL-8, and interferon-a. PAF metabolizing enzymes have not been purified and fully characterized from brain tissue. However, many studies indicate that PAF synthesis and degradation occur in mammalian brain [176–178]. Thanks to use of high-performance liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS), nineteen 1-alkyl,2acylglycerophosphocholine species were identified in the brain, three of which were significantly elevated in AD cortex: 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF), its immediate metabolite/precursor 1-O-hexadecyl-sn-glycero-3phosphocholine (C16:0 lyso-PAF), and 1-O-oleyl-2-lyso-sn-glycero-3-phosphocholine (C18:1 lyso-PAF) [179]. PAF species are synthesised through two pathways: or by oxidation of structural membrane glycerophosphocholines or enzymatic modification of glycerophosphoethanolamines. PAFs mediate an array of biological processes and are very abundant in the mammalian CNS, where they act as synaptic messengers, transcription inducers, and are involved in LTP [180]. The majority of PAF effects are attributed to interaction with a single G protein-coupled receptor (PAFR), expressed by multiple peripheral cell types but regionally restricted to microglia subpopulations in the CNS [181]. Furthermore, PAFs were reported to act in receptor-dependent and -independent manners and this is related also in a species-specific way given that both PAFR-expressing and PAFR-deficient neurons are sensitive to the neurotoxic effects of PAF ligands [179]. The length of the sn-2 carbon chain dictates PAFR affinity while the sn-1 ether linkage is not required for PAFR interaction even if does increase potency several hundred-fold [182]. The sn-1 carbon

chain length and the degree of unsaturation is implicated in activation of different PAFR signaling pathways [183]. In fact, some studies showed positive effect of PAF molecules on neuronal function whereas other studies, exalting the protective effect of PAF antagonists, did not seem to confirm the first hypothesis. Under physiological conditions, PAFs act as retrograde neurotransmitters, contributing to hippocampal CA1 LTP by enhancing excitatory synaptic transmission [184,185]. One form of hippocampal LTP depends on activation of the NMDA receptors and subsequent entry of calcium into the post synaptic cell. This postsynaptic event is considered to modify presynaptic transmitter release more probably by the existence of retrograde messengers that travel from the postsynaptic cell to the presynaptic terminal. In this mechanism, PAF species have been considered to play an important role because LTP in the hippocampal CA1 region was blocked by a PAF antagonist (BN 52021) in hippocampal slices. Izquierdo and colleagues demonstrated a positive effect of PAF on memory formation in vivo by infusing mc-PAF into rat hippocampus, amygdala, or entorhinal cortex showing an augmented excitatory postsynaptic current in primary cultures of rat hippocampal cells [186]. Ishii and colleagues re-examined a possible contribution of PAF to LTP by using two structurally different PAF antagonists BN 52021 and TCV-309 on mice not revealing any effects on murine LTP as well as any detectable changes in excitatory synaptic transmission after application of PAF. This, taken together with normal LTP formation in PAFR-deficient mice, suggested that PAFR is not required for murine LTP in the CA1 region [187]. The reason for the conflicting pharmacological results between these studies could be related to different experimental conditions given that some authors used mice [187], whereas others used rats [186]. Increased PAF content was also detected in a culture medium of primary neuronal cultures of rat cerebral cortex treated with a neurotoxic concentration of glutamate [188]. In this study NMDA activated MAPKs, including c-Jun N-terminal kinase/stressactivated protein kinase (JNK/SAPK), ERK, and p38 subtypes, and elicited apoptotic cell death in primary rat hippocampal neuronal cultures [189,190]. PAF intervened in these activities of NMDA in a manner that was sensitive to plasma-type PAF acetylhydrolase or to PAF antagonist BN 50730. Interestingly, activation of metabotropic glutamate receptor (mGluR) attenuated this NMDA receptor–PAF–MAPK signaling pathway [190]. Protection against the glutamate-neurotoxicity was provided by PAF antagonists (BN 52021, CV-6209, and E5880) and anti-PAF IgG. In fact, NMDA antagonists MK801 and memantine were reported to ameliorate PAF-induced neurotoxicity against primary human fetal cortical or rat postnatal retinal ganglion neurons [191]. The PAF effects were significantly attenuated by treatment with PKC inhibitor H7, calcium-calmodulin kinase II inhibitor KN-62, or tyrosine kinase inhibitor methyl 2,5-dihydroxycinnamate, suggesting that phosphorylation of both serine/threonine and tyrosine residues in NMDA receptors or their associated molecules may be implicated in PAF-induced potentiation of NMDA receptor currents [187]. Kinase receptor signaling, which also leads to the activation of JNK/ SAPK, ERK, and p38 kinases as well as neuronal cell death, was revealed to use PAF as a downstream messenger [187]. Another plausible explanation to these conflicting results about the PAF role in neuronal activity is related to isoform specificity of PAF, according to the possible different role of the long-chain sn-1 fatty acid in regulating PAF-induced caspase-dependent apoptosis, caspaseindependent neurodegeneration, and neuroprotection in the presence or absence of the PAFR [183]. Therefore, heterogeneity in the sn-1 carbon chain of PAF could determine pro- or anti-apoptotic signaling in primary neurons. Again, this aspect highlights how may be important the diet role in modifying the lipid membranes composition, shifting the balance’s needle from negative to positive effects, and viceversa. An

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interesting study showed that the carbon chain length at the sn-1 position dictates whether neurons undergo caspase-dependent apoptosis, caspase-independent neurodegeneration, or are protected from PAF toxicity [183]. This study suggested that in PAFR-deficient neurons, submicellar concentrations of C16-PAF initiated a caspase-dependent apoptotic death cascade, whereas C18-PAF signaled caspase-independent degeneration. Conversely, PAFR activation by C16-PAF protected cells from PAF challenge, whereas PAFR activation by C18-PAF signaled pro-apoptotic caspase activation. Collectively, these data implicated heterogeneity in the sn-1 carbon chain of PAF species in controlling neuronal life, with signaling dependent upon PAFR expression profile [183]. Using an unbiased lipidomic approach to identify metabolic disruptions in alkylacylglycerophosphocholine second messengers in the posterior-entorhinal cortex of AD patients, TgCRND8 transgenic mice, as well as human neurons directly exposed to soluble Ab1–42 oligomers, some authors found that Ab1–42 triggers a selective destabilization in Land’s cycle metabolites defined by a palmitic acid (16:0) at the sn-1 position [183]. The acute accumulation of C16:0 PAF, but not its immediate precursor and metabolite C16:0 lyso-PAF, signals the phosphorylation of tau at AD-specific epitopes. Chronic elevation activates an ER-associated calpain and caspase cascade compromising neuronal viability. Strategies that either promotes the hydrolysis of C16:0 PAF to C16:0 lyso-PAF or inhibit downstream signal transduction pathways protect neurons from Ab1–42 toxicity and prevent aberrant tau processing [183]. In progressive neurodegenerative disorders, PAF concentrations increased as a result of enhanced PLA2 activity [23,192]. Inhibition of the PAF remodeling pathway through dietary consumption of the n-3 PUFA DHA [193] blocked PAFmediated apoptosis in non neural cells [194], and reduced dendritic pathology in transgenic models of AD [195]. Furthermore, PAF could enhance the Ab toxicity by Ca2+ dyshomeostasis. In fact, using hippocampal neuronal cultures, it was found that PAF was able to reproduce each event in the neuroapoptosis cascade, including Ca2+ influx via NMDA receptors, enhancement of Ca2+ response to NMDA via activation of PKC, increase of extracellular concentrations of glutamate, and increase in cytosolic free Ca2+ [196]. Moreover, each of these events could be blocked by Ginkgo biloba extract EGb761, a free radical scavenger with PAF antagonism, and by quercetin, a constituent with well-established free radical scavenging property, both present in the nutrients of Mediterranean diet [18].

LOX), and generates 12-hydroperoxyeicosatetraenoic acid glyceryl ester (12-HETE-GE) and 15-hydroperoxyeicosatetraenoic acid glyceryl ester (15-HETE-GE), respectively [199,200]. These metabolites mediate their biological activities via established receptors, including the cannabinoid receptors, PPAR-c, and transient receptor potential vanilloid 1(TRPV1) receptor [200,201]. Ab-induced brain damage in AD is not only accompanied by release of ECs from neurons and glial cells, but also by increase in ERK activity, the induction of brain-derived neurotrophic factor (BDNF), and the activation of CB1-mediated neuroprotective pathways [202,203]. Activated microglial cells in AD also express significant levels of cannabinoid CB2 receptors, which may trigger CB2-dependent pro-inflammatory cytokine release and neuroinflammation [204,205]. Association of EC-mediated neuroinflammation in AD is supported by high activity of fatty acid amide hydrolase (FAAH) in astrocytes surrounding SPs. The hydrolysis of AEA and 2-AG by FAAH generates AA, which is oxidized to eicosanoids that in turn enhance neuroinflammation. Surprisingly, intracerebroventricular administration of the synthetic cannabinoid (WIN55, 212-2) in rats prevents Ab-induced microglial activation, cognitive impairment, and loss of neuronal markers. Other synthetic cannabinoids (HU-210 and JWH-133) prevent Ab-mediated activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and TNF-a release. These effects appear to be independent of the antioxidant action of cannabinoid compounds and are also induced by a CB2-selective agonist. Moreover, cannabinoids abrogate microglia-mediated neurotoxicity after Ab addition to rat cortical cultures [206]. It is suggested that cannabinoid receptors may be associated with the AD pathology and that synthetic and plant cannabinoids may have beneficial effects on neurodegenerative process in AD [206].

2.1.5. Cannabinoids in Alzheimer’s disease ECs are AA-containing metabolites that bind to the cannabinoid receptors and mimic several pharmacological effects of d-9-tetrahydrocannabinol, the active principle of Cannabis sativa preparations, such as hashish and marijuana. Major ECs, which are generated during GP metabolism include anandamide (arachidonyl-ethanolamide, AEA) and 2-arachidonoylglycerol (2-AG). They induce their action through specific 7-transmembrane domain G protein-coupled receptors called cannabinoid receptors. Three cannabinoid receptors, namely CB1, CB2, and CB3 have been reported to occur in the hippocampus, neocortex, basal ganglia, cerebellum, and anterior olfactory nucleus [197]. CB1 receptors are mostly expressed in neurons, where they regulate neurotransmitter release and synaptic strength whereas CB2 receptors are found mostly in glial cells and microglia. CB1 and CB2 receptors are involved in neuronal cell proliferation, migration, differentiation, morphogenesis and synaptogenesis [198]. AEA is oxidized by COX-2, 12-LOX, and 15-LOX resulting in the generation of prostaglandin E2 ethanolamide (PGE2-EA), 12-hydroperoxyeicosatetraenoic acid ethamolamide (12-HETE-EA), and 15-hydroperoxyeicosatetraenoic acid ehanolamide (15-HETE-EA), respectively. Similarly, 2-AG is metabolized by 12-lipoxygenase (12-LOX) and 15-lipoxygenase (15-

2.2.1. 4-Hydroxynonenal in Alzheimer’s disease 4-HNE is a major end-product of AA peroxidation. This nine carbon a, b-unsaturated aldehyde contains three functional groups, which often act in concert and help to explain its high reactivity [207–209]. 4-HNE not only reacts with free cysteine, histidine and lysine, but also cysteine, histidine and lysine in proteins and peptides leading to the formation of stable Michael adducts with a hemiacetal structure [208–211]. In addition, 4-HNE also reacts with DNA, and phospholipids, generating a variety of intra- and inter-molecular covalent adducts. This aldehyde also acts as bioactive lipid mediator that produces rapid cell death not only through the depletion of sulfhydryl groups, but also through alterations in calcium homeostasis [208–211]. At low concentrations, 4-HNE affects many enzymes (phospholipases A2, C, and D, protein kinases, COXs, ATPases, adenylate cyclases, and NOS) associated with cell growth, gene expression, LTP, inflammation, apoptosis, and BBB permeability. High concentration of 4-HNE during the initial stages of oxidative injury can exacerbate the cellular oxidative damage cascade not only by altering mitochondrial function and redox status and decreasing ROS clearance [210,212], but also by electrophilically attacking the nucleophilic sites on proteins [210]. Thus, treatment of PC12 cells with

2.2. Non-enzymic lipid mediators of arachidonic acid and docosahexaenoic acid metabolism in Alzheimer’s disease Lipid peroxidation-mediated breakdown of AA and DHA leads to the formation of a number of aldehydes by-products, including 4-HNE, 4-HHE, IsoPs, NPs, IsoKs, NK, IsoFs, NFs, acrolein, and malondialdehyde (MDA) [23]. Levels of aldehydes by-products are markedly increased in brain and CSF of AD patients. The most abundant aldehydes are 4-HNE and MDA, while acrolein is the most reactive. Several of these aldehydes are rapidly incorporated into proteins to generate carbonyl derivatives.

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4-HNE induces oxidative stress by compromising the mitochondrial redox metabolism [212]. These processes are accompanied by marked inhibition of mitochondrial respiratory enzymes, cytochrome c oxidase and aconitase, and by increase in nuclear translocation of NF-kB/p65 protein leading to up-regulation of TNF-a. In addition, 4-HNE releases mitochondrial cytochrome c, activates poly-(ADP-ribose) polymerase leading to DNA fragmentation, and decreases expression of anti-apoptotic BCL-2 proteins. Collective evidence suggests that 4-HNE-induced cytotoxicity may be associated, at least in part, with the altered mitochondrial redox, mitochondrial energy metabolism, membrane dynamics, and respiratory dysfunctions that ultimately may lead to apoptotic cell death [208–212]. In AD, Ab-mediated damage is accompanied by the stimulation of PLA2 activity, release of AA, and formation of 4-HNE [51]. 4-HNE co-localizes with intraneuronal NFTs and may contribute to the cytoskeletal derangement found in AD. It is shown that expression and activity of BACE1 is increased by 4-HNE and that there is a significant correlation between BACE1 activity and oxidative markers in sporadic AD [213]. 4-HNE may also mediate the degeneration of neurons by modifying membrane-associated glucose and glutamate transporters, ion-motive ATPases, enzymes involved in amyloid metabolism, and cytoskeletal proteins. Detailed investigations on patients with cognitive disorders using a proteomic approach indicate that there is a marked elevation in proteinbound 4-HNE, including ATP synthase, a-enolase, aconitase, aldolase, glutamine synthetase, Mn-superoxide dismutase and proteins like peroxiredoxin 6, dihydropyriminidase related protein-2, and a-tubulin [214]. These enzymes and proteins are associated with glucose metabolism, maintenance of glutamate levels, antioxidant defense systems, axonal growth, and maintenance of cytoskeleton [215]. Free 4-HNE levels were found to be significantly elevated in the ventricular fluid of AD patients compared with control subjects [216] (Table 1). In addition, neprilysin, a major protease which cleaves Ab in vivo, forms adducts with 4HNE leading to decrease in its activity in the brain of AD patients and cultured cells [217]. Treatment with N-acetylcysteine results in sparing of neprilysin from oxidative modification, suggesting a potential mechanism underlying the neuroprotective effects of antioxidants in AD [217]. 4-HNE also binds to histones and this binding alters the ability of the histone to bind DNA. It is proposed that alterations in DNA-histone interactions may contribute to the vulnerability of neurons in AD brain [218]. 4-HHE is a peroxidation product of DHA. Like 4-HNE, 4-HHE has a conjugated double bond between the a and b carbon, so the c carbon of 4-HHE is electron deficient and reacts readily with nucleophiles such as thiols and amines, whereas the carbonyl group forms a Schiff base with amino groups such as N-termini of proteins and the e-amino group of lysine [219,220]. Levels of extractable and protein-bound 4-HHE are elevated in hippocampus/ parahippocampal gyrus of patients with MCI, preclinical AD, and later stage of AD compared to age-matched normal control subjects supporting a crucial role for lipid peroxidation in the progression of AD [221] (Table 1). 2.2.2. Isoprostanes, neuroprostanes, isofurans, neurofurans, isoketals, and neuroketals in Alzheimer’s disease Although IsoPs are PG-like mediators generated by free radicalcatalyzed peroxidation of esterified AA in vivo, they differ from PGs in several ways. Thus, in IsoPs side chains are predominantly oriented cis to the cyclopentane (prostane) ring while in PGs side chains they are exclusively in trans orientation [222]. A second important difference between IsoPs and PGs is that IsoPs are formed primarily in situ esterified to phospholipids and are subsequently released by a PLA2 [223,224], while PGs are generated only from free AA, which is oxidized by cyclooxygenase reaction

[35,225]. IsoPs are reliable biomarkers for oxidative stress. The minimum requirement for the synthesis of IsoPs is a PUFA with 3 contiguous, methylene-interrupted double bonds [226–228]. Four classes of F2-isoPs can be obtained from AA [225,229–231]. Each of these classes comprise up to eight racemic isomers, leading to a large number of IsoP molecular species. In addition, IsoPs act as important lipid mediators that modulate not only excitatory neurotransmission, but several other biochemical processes, including vasoconstriction in brain microvasculature, epithelial cell permeability, and up-regulation of cytokine expression at nanomolar concentrations [232,233]. Moreover, AA-derived F2-IsoPs produce their effect on the vascular bed by inducing the generation of TX in the endothelium, which not only facilitate the contraction in the vascular smooth muscle, but also promotes endothelial cell death [234]. Levels of IsoPs are significantly increased in brain and CSF from AD patients [235,236] (Table 1). Treatment of neuronal preparations with Ab peptide increases the synthesis of F2-IsoP [237,238]. In a mouse model of AD significant increase in F2-IsoPs precedes SP formation [239,240]. Administration of F2-IsoP into the brains of Tg2576 mice leads to increase in Ab levels in the brain. Increase in Ab levels and plaque-like deposits, can be blocked by a TXA2 receptor antagonist, suggesting that TXA2 receptor activation is associated with the effects of F2-IsoP on Ab [241]. Non-enzymic oxidation of DHA generates NPs [242], which are 22 carbons and 4 double bonds containing prostaglandin-like metabolites. They contain a substituted tetrahydrofuran ring and, like IsoPs, NPs are also reliable biomarkers of oxidative stress. NPs are also synthesised in situ esterified to phospholipids and are subsequently released by a PLA2. NPs containing phospholipids and free NPs induce changes in neural membrane fluidity and permeability. These changes may lead to impairment in neuronal function and promote oxidative stress and neurodegeneration [225,243,244]. A number of different F4-NP regioisomers are formed from the peroxidation of DHA. They include eight possible regioisomeric groups, 4- and 20-series NPs. Unlike AA-derived IsoPs, only limited studies has been performed on non-enzymatic oxidation of DHA, so little is known about biochemical effects of NPs in neural and non-neural tissues. NPs occur in CSF from normal individuals. The levels of F4-NP are significantly increased in CSF from AD patients [242,245]. E4-NP and D4-NP are also detected in normal rat and human brain. Levels of E4/D4-NP in normal brain are found to be one-third compared to levels of F4-NP [246]. IsoKs are c-ketoaldehydes generated via the isoprostane pathway of AA peroxidation, and are among the most reactive byproducts of lipid peroxidation. IsoKs differ from IsoPs for their characteristic aldehydic group in a 1,4-dicarbonyl array, making them extremely reactive toward primary amino groups in proteins [247,248]. Unlike F2-IsoP, isoKs can modify biologically important proteins rather than to active specific receptors [249]. IsoKs form adducts with proteins and PE in vitro. The ability of isoketals to covalently modify PE is greater than that of 4-hydroxynonenal. IsoK-PE adduct mediates some of the biological effects of IsoKs relevant to physiological processes and it is becoming increasingly evident that their levels are increased in neuodegenerative diseases including AD [250], however, the neuropathological processes remains still under investigation [251]. Presence of NKs as products of NPs pathway in brain tissue has also been reported [252]. They form adducts with lysine residues and rapidity induce cross-linking. NKs have either a 1,4-pentadiene or 1,4,7-octatriene side chain structure, which can undergo further oxidation to form NKs with an additional hydroxyl group [252]. Collective evidence confirms this event, therefore suggesting that the measurement of only unoxidized NK adducts likely underestimates the amount of NK adducts present in the brain in neurological disorders with

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oxidative stress [252]. At the moment, no information is available on levels of NK in AD brain. Lipid peroxidation of AA under high oxygen tension generates substituted tetrahydrofuran derivatives called as IsoF [253]. Although the molecular basis of isofuran generation is not fully understood, two mechanisms (a cyclic peroxide cleavage pathway and an epoxide hydrolysis pathway) have been proposed. Oxygen concentration modulates the generation of IsoFs. Increased oxygen concentrations favors the formation of isoFs and delays the formation of isoP. Levels of IsoFs are increased significantly in AD patients compared to age matched control subjects [254]. NFs are 22-carbon compounds that are generated nonenzymic oxidation of DHA. Similarly to isoFs, Nfs contain a substituted tetrahydrofuran ring, and are formed under severe oxidative stress. Levels of NFs are elevated in the brain cortex of a mouse model of AD [255]. 2.2.3. Acrolein and malondialdehyde in Alzheimer’s disease As stated above, lipid peroxidation leads to the formation of a number of aldehydes by-products, including acrolein and MDA. Among aldehydes by-products acrolein is the most reactive aldehyde [210]. The pronounced toxicity of acrolein reflects its ability to alkylate nucleophilic centers in macromolecules. Acrolein reacts with cysteine, histidine, and lysine residues of proteins. Its incorporation into proteins generates carbonyl derivatives [208]. It also reacts with nucleophilic sites in DNA. This reaction results in modification of DNA bases through the formation of exocyclic adducts. Acrolein produces toxic effects in brain tissue by binding to proteins and inducing mitochondrial oxidative stress [256,257]. Acrolein-mediated neurotoxicity is accompanied by significant impairment of adenine nucleotide translocase activity and of glucose and glutamate uptake in primary neuronal cultures [257,258]. Glutathione and N-acetylcysteine can prevent acroleinmediated inhibition of mitochondrial oxidative stress. Proteinbound acrolein is a powerful marker of oxidative protein damage which plays an important role in the formation of NFTs in AD [259]. Serum MDA levels were significantly higher in AD patients than in control subjects [260] (Table 1). Furthermore, in AD brain, levels of acrolein are increased in hippocampus and temporal cortex where oxidative stress is high. In late-onset AD, a 2-fold increase in levels of acrolein/guanosine adducts in nDNA have been isolated from the hippocampus of AD as compared to age-matched control. These adducts may promote DNA-DNA and DNA-protein crosslinking while 4-HNE/guanosine adduct in nDNA was not elevated in AD [261] (Table 1). In AD, glutathione-S-transferase activity, the main enzyme responsible for the detoxification of acrolein, is significantly reduced in hippocampus. 3. Molecular mechanism associated with lipid mediatormediated neurodegeneration in Alzheimer’s disease It is becoming increasingly evident that metabolism of neural membrane GPs, sphingolipids, and cholesterol are closely interrelated and interconnected. For example, GP-derived lipid mediators (AA) modulate sphingolipid metabolism by modulating sphingomyelinases, and sphingolipid-derived lipid mediators (ceramide, ceramide 1 phosphate), and regulate GP metabolism by modulating isoforms of PLA2 [23]. Moreover, many cellular stimuli modulate more than one enzyme at the same time, thus adding to the complexity of regulation of GP and sphingolipid metabolism. Under normal conditions, the basic status of enzymes of both GP and sphingolipid metabolism in neural cell regulation as well as the proposed role for these enzymes in integration of cellular responses, are based not only on levels of GP- and sphingolipidderived lipid mediators and organization of signaling network,

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but also on the complexity and interconnectedness of their metabolism [31]. As above mentionated, AD is accompanied not only by the accumulation of Ab, but also by increased oxidative stress and neuroinflammation [40]. Both these processes are interconnected to each other. Oxidative stress in AD produces several effects that may contribute to neuroinflammation, synaptic dysfunction, memory loss, and cell death. The expression and activity of BACE1 is increased by oxidant agents and by AA-derived lipid mediator, namely 4-HNE, and there is a significant correlation between BACE1 activity and oxidative markers in sporadic AD (Fig. 3). Elevation in oxidative stress and neuroinflammation caused by Ab-mediated generation of ROS, stimulation of PLA2 isoforms, and increase in generation of GP-derived lipid mediators (eicosanoids and PAF) may contribute to delayed neuronal death in AD. Furthermore, cortical synaptosomes show a decrease in ability to detoxify lipid peroxides in AD, including AA-derived 4-HNE [262], supporting the view that a decreased antioxidant defense may play a role in AD pathophysiology [263]. Studies on synaptosomal preparations of the frontal cortex in AD demonstrate elevated levels of 4-HNE, acrolein, and other GP-derived lipid mediators, suggesting that the antioxidant defenses and generation of anti-inflammatory docosanoids have not been able to offset oxidative stress and neuroinflammation. The ability of 4-HNE, acrolein and other GP-derived lipid mediators to inhibit key mitochondrial enzymes may increase ROS release into the cytoplasm [264], and downstream effects of mitochondrial dysfunction inducing the loss of synaptic function, abnormal inflammatory and immune responses, and neuronal death in AD [265]. These observations provide further insight into the relationship among synaptic dysfunction, mitochondrial oxidative stress, and the progression of cognitive changes in AD brain. Oxidative stress related damage to nucleic acids has been suggested as a prime contributing factor in the disease progression as a result of mistakes in base pairings resulting in compromised transcription and translation [266]. In addition, marked elevation in levels of GP- and sphingolipid-derived lipid mediators in AD may disturb the signaling networks, so resulting in loss of communication between GP and sphingolipid metabolism. This loss of communication may also threaten the integrity of asymetric lipid bilayer and lipid homeostasis, initiating neural cell death and cognitive impairment [23,31,38]. Induction of lipid mediatormediated oxidative stress may also result in several other cellular processes, such as aging, hyperglycemia, and hypoxia, which are all well known risk factors for the development of AD.

4. Conclusions Presence of various combinations of polar headgroups, fatty acyl chains, and backbone structures makes neural membrane GPs complex molecules, which perform diverse functions, including apoptosis, membrane fusion, regulation of enzyme activities, and ion transport. Neural membranes are interactive and dynamic. The interaction of many agonists with their receptors produces enrichment in GP metabolism and results in the regulation of activities of membrane-bound enzymes, receptors, and ion-channels. Enhanced degradation of neural membrane GPs by PLA2s in AD results in generation of enzymic and non-enzymic lipid mediators of AA (eicosanoids, PAF, IsoPs, and 4-HNE), which may promote not only the accumulation of Ab, and an abnormal interplay with lipid mediators of sphingolipid and cholesterol metabolism, but also induction of oxidative stress, and chronic neuroinflammation. These processes are closely linked to each other and may contribute to changes in neural membrane fluidity, permeability, Ca2+ influx, and mitochondrial and synaptic dysfunctions through the inactivation of mitochondrial enzymes leading to

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neurodegeneration. In contrast, enzymatic oxidation of DHA generates docosanoids, which not only down-regulates proinflammatory cytokines, but also have anti-inflammatory, antithrombotic, anti-arrhythmic, and vasodilatory processes, which facilitate neuroprotection. Although some progress has been made on GP composition of neural membranes and lipid mediators in AD, little is known about brain GP and GP-derived lipid mediator trafficking and sorting in neurodegenerative disorders. Enzymes of docosanoid metabolism and receptors have been characterized in brain tissue. Molecular biology approaches, such as cloning the cDNA for enzymes of GP metabolism, will advance the understanding at cellular and subcellular levels of the potential importance of GP metabolism in the normal and AD brain. Collective evidence suggests that more studies are needed on enhanced GP metabolism and its contribution to the pathogenesis of AD. In this complex GP meshwork, the search for a suitable modulating enzyme able to shift the metabolic pathway towards a neuroprotective role as well as a better knowledge about how lipid dietary modulation could intervene into slowing the neurodegenerative processes, could be an essential step to delay the AD onset and progression or to possibly track new therapeutic options.

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