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Logo of agdisAging and DiseaseAboutEditorial BoardSubmissionAchieves
Aging Dis. Aug 2010; 1(1): 37–59.
Published online Jul 12, 2010.
PMCID: PMC3295019

Alzheimer’s Disease: Fatty Acids We Eat may be Linked to a Specific Protection via Low-dose Aspirin

Abstract

It has been suggested that cognitive decline in aging is the consequence of a growing vulnerability to an asymptomatic state of neuroinflammation. Moreover, it is becoming more evident that inflammation occurs in the brain of Alzheimer’s disease (AD) patients and that the classical mediators of inflammation, eicosanoids and cytokines, may contribute to the neurodegeneration. In agreement with this observation, aspirin (ASA) - a non-steroidal anti-inflammatory drug - may protect against AD and/or vascular dementia. However, both the time of prescription and the dose of ASA may be critical. A major indication for low-dose ASA is in combination with docosahexaenoic acid (DHA). DHA plays an essential role in neural function and its anti-inflammatory properties are associated with the well-known ability of this fatty acid to inhibit the production of various pro-inflammatory mediators, including eicosanoids and cytokines. Higher DHA intake is inversely correlated with relative risk of AD and DHA+ASA supplement may further decrease cognitive decline in healthy elderly adults. Although low-dose ASA may be insufficient for any anti-inflammatory action the concomitant presence of DHA favours a neuroprotective role for ASA. This depends on the allosteric effects of ASA on cyclooxygenase-2 and following production - from DHA - of specific lipid mediators (resolvins, protectins, and electrophilic oxo-derivatives). ASA and DHA might protect against AD, although controlled trials are warranted.

Keywords: Cytokines, docosahexaenoic acid (DHA), aspirin (ASA), resolvins, neuroprotectin D1 (NPD1), nonsteroidal anti-inflammatory drugs (NSAIDs), primary prevention

Aging is a complex multifunctional process inherent to molecular and structural changes, as a low-grade chronic up-regulation of certain inflammatory responses [1]. Advancing age remains the major risk factor for decline in memory functions and, ultimately, for Alzheimer’s dementia (AD) (Figure 1). It has been suggested that cognitive decline in aging is the consequence of a growing vulnerability to an asymptomatic state of neuroinflammation, which may differ radically from traditional acute inflammation [2]. This systemic neuroinflammatory response is supported by augmented serum levels of pro-inflammatory cytokines [3]. A prominent astrogliosis, mostly observed in the cells surrounding amyloid plaques, is present in Alzheimer’s brains [4] and Alzheimer itself originally suggested the pathological potential of glial cells in progression of dementia [5]. Degradation of beta-amyloid (Aβ) protein by astrocytes has been documented in AD brains [6], but the accumulation of Aβ in astrocytes causes gliosis [4,7]. The importance of this inflammatory reaction is clear considering the central, structural and physiological functions that astrocytes carry out in the normal brain. Their presence contribute to : 1) the structural integrity of the blood-brain barrier (BBB) - possibly participating in the exchange between the blood and brain parenchyma [8]; 2) making extensive contacts with the surfaces of adjacent neurons [9]; 3) ensuring normal neuronal excitability and synaptic transmission [10], and increasing the number of mature, functional synapses and central nervous system (CNS) neurons [11]. Consistent with these indications, several observational studies (for a review see [12]) have shown that use of various nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of developing AD. Nevertheless, after preliminary studies provided encouraging results, a series of larger trials - that tested NSAIDs on patients with AD and mild cognitive impairment (MCI) - reported negative results [1315].

Figure 1.
Old age is associated with an enhanced susceptibility to neuroinflammatory response and glial activation which is a component of AD [177]. Acute cognitive impairment may result from infections that are unrelated to the central nervous system. Activation ...

However, the protective action of NSAIDs may be more complex than for long broadly believed. For example, aspirin (ASA) - in presence of selected omega-3 (n3) polyunsaturated fatty acids (PUFAs) - triggers the biosynthesis of a new group of mediators - resolvins and protectins [16], and oxoderivatives [17] - that may indeed exert neuroprotection [18]. This review reports observations on the possible use of low-dose ASA and DHA for primary prevention in Alzheimer’s.

Changes associated with Alzheimer’s disease

Alzheimer brain histopathology includes neurofibrillary tangles (NFTs) of tau protein within neurons, extracellular deposits of the Aβ in senile plaques and the loss of synaptic connections manifested as brain atrophy [19]. However, NFTs appear in multiple brain diseases, and are not specific for AD, particularly if a broader definition of NFTs is used [20]. Unlike NFTs, the appearance of amyloid plaques in AD brains is unique and the particular appearance of neuritic plaques (i.e., Aβ peptide–containing extracellular lesions surrounded by tau neurofibrillary pathology) is considered to be specific for AD. In spite of this, these changes can only be evaluated in the postmortem brain. For this reason, current diagnosis uses clinical analyses and neuroimaging to detect “possible AD”. Imaging techniques include: 1) Positron emission tomography - to identify cerebral glucose metabolic rate characteristic of AD [21,22] - as well as magnetic resonance imaging, which allows the identification of brain atrophy correlated with AD [21,23,24]. The hippocampus and entorhinal cortex may be severely involved in early AD [25,26] whereas neocortical areas are still relatively well preserved. Aβ oligomers are believed to have neurotoxic effects [27], and to promote NFT formation [,28]. Aβ is produced from the amyloid β protein precursor (APP) through sequential proteolytic cleavages (Figure 2). APP is first cleaved by a membrane-bound aspartyl protease (referred to as β-secretase). This cleavage generates a large secreted derivative (sAPPβ) and a membrane-bound APP carboxy-terminal fragment (CTFβ); cleavage of CTFβ by γ-secretase results in the production of Aβ peptides of varying length. The two species of most interest are a 40–amino acid Aβ peptide (Aβ1–40) and a 42–amino acid Aβ peptide (Aβ1–42) [,28].

Figure 2.
Cleavage of amyloid β protein precursor (APP) by β-secretase (β-site of APP cleaving enzyme, BACE 1) generates a large β-secreted derivative, sAPPβ, and an Aβ-bearing membrane-associated C-terminal derivative, ...

Aging and Inflammation

Cognitive decline with aging may result from a combination of inflammation and vascular lesions. For elderly patients, the Rotterdam Study has indicated that vascular risk factors, and indicators of vascular disease have an established association with Alzheimer’s [29]. The same conclusion was reached by de la Torre [30]. There are additional examples.

Firstly, human brain microvessel endothelial cells exposed to transient hypoxia secrete interleukin (IL)-1β at concentrations which are known to induce Aβ peptide release from human neural cells [31].

The ‘amyloid hypothesis’ [32] establishes that a build-up of Aβ protein is responsible for neural dysfunction and neuronal loss in brain regions supporting memory function (Figure 2). In agreement with this conclusion memory impairments in normal elderly and early AD patients are intimately related to hypoxia - that is a reduction in blood supply - in the hippocampus and a number of key brain areas [33].

Secondly, the nuclear factor-kappa beta (NF-κB) signaling - that may accelerate the aging process - is the main mediator of inflammation and endothelial dysfunction in the elderly [34,35] (Figure 3 and and4).4). Many longevity genes, e.g. SIRT1, are inhibitors of NF-κB signaling, as well as natural antioxidants and anti-inflammatory molecules, such as curcumin [36] and resveratrol [37].

Figure 3.
Pathways contributing to the promotion of a persistent inflammatory state [184]. Increasing evidence has demonstrated that impaired nitric oxide (NO) bioactivity has critical role in the pathogenesis of vascular dysfunction. NO production in endothelial ...
Figure 4.
Activation of the nuclear factor kappaB (NF-κB) directly correlates with endothelial dysfunction. During the normal aging process, proteins are progressively and irreversibly modified with advanced glycation end products (AGEs), by nonenzymatic ...

The activation of the transcription factors NF-κB results in the expression of pro-inflammatory cytokines such as IL-6, IL-1 and tumor necrosis factor (TNF)-α. Some of the NF-κB-induced proteins - which are particularly important in the chronic inflammatory state - are also its activators [38]. On the whole, NF-κB is part of a genetic switch which controls the gene expression of cytokines, chemokines, growth factors, and cell adhesion molecules as well as some acute phase proteins [39]; NF-κB has been identified in numerous cell types and is found to be activated by a wide range of inducers, including ultraviolet irradiation, cytokines, inhaled occupational particles, and bacterial or viral products.

Thirdly, autocrine/paracrine TNF-α is a potent pro-inflammatory mediator, which has several important functions within the CNS [40] including microglial and astrocyte activation [41], and synaptic plasticity [42]. Microglia, astrocytes and some neurones each produce and respond to TNF-α in characteristic way when the brain is injured [4347]. For example, TNF-α can protect neurons against oxidative insults and may, consequently, serve neuroprotective roles. Alternatively, under certain conditions, TNF-α can promote damage of neuronal and glial cells, elicit neurodegeneration [48] and contribute to the pathogenesis of disruption of the BBB during brain inflammation [49]. Previous studies have suggested that, in the elderly, circulating plasma levels of TNF-α are elevated [50] and high levels of TNF-α and IL-6 are associated with increased truncal fat mass, suggesting that cytokines are partly derived from the adipose tissue [51]. Consistent with this observation, with aging adipocytes develop an inflammatory state, which promotes a higher expression of inflammatory cytokines IL-1β, IL-6, and TNF-α by macrophages and thus, further propagates inflammation [52].

In carotid arteries of young animals, recombinant TNF-α induces endothelial dysfunction [53, 54] and increases pro-inflammatory gene expression, mimicking many of the symptoms of vascular aging [55] (Figure 5). The first indication of contribution of TNF-α signaling in AD was the presence of this cytokine on amyloidogenic plaques in post-mortem analysis of AD brains [56]. Additionally, Gao and co-workers [57] reported that TNF-α may impair NO-mediated vasodilation.

Figure 5.
Role of tumor necrosis factor (TNF)-α in age-related vascular endothelial dysfunction [34,53,54, 182,191195]. Both AGE (advanced glycation end-product)/RAGE (receptor for AGEs) and nuclear factor-kappa B (NF-κB) signalling play ...

This complex interplay between aging, endothelial function and CNS physiology is indicative of a crucial operative interaction that occurs between the brain and the immune system, also considering that in aging the balance between pro-inflammatory and anti-inflammatory cytokines, shifts into a consistent pro-inflammatory state [5860]. Microglia and astrocytes, innate immune cells of the brain, become more reactive during normal aging [61]. This age-associated increase in innate immune reactivity sets the stage for an exaggerated inflammatory cytokine response in the brain after activation of the peripheral innate immune system. This elevated neuroinflammatory response may lead to more severe long-lasting behavioral and cognitive deficits [60,62]. For example, individuals with very high plasma IL-6 levels could have a greater tendency to exhibit a poorer baseline cognitive function and progress more frequently to cognitive impairment [62].

The importance of inflammatory mechanisms in Alzheimer disease

In the elderly, microglia and astrocytes, become more reactive [61], and this increased cellular reactivity may be both a key mediator of aged-related neuroinflammation and an increased risk of cognitive impairment [60, 62]. In addition to the secretion of cytokines, activated microglial cells produce toxic molecules such as nitric oxide (NO) and prostaglandins (PGs), which might further contribute to the decay. Eventually, in conjunction with the secretion of cytokines, microglia cells interfere with astroglial functions, levels of vascular endothelial growth factor and intercellular adhesion molecule 1 [63] and increase the permeability of the blood-brain-barrier (BBB) [64]. Many of the cytokines and chemokines that have been studied in AD, including IL-1β, IL-6, IL-8, the TNF-α, the transforming growth factor (TGF)-β and macrophage inflammatory protein-1α, have been found to have an altered expression compared with control subjects [65]. IL-1 is associated with Aβ in senile plaques [66] and also increases the synthesis and translation of the mRNA for APP, the processing of which produces Aβ [67]. Richartz et al. [68] have reported a reduced production of the pro-inflammatory cytokines IL-6, IL-12, IFN-γ, and TNF-α in whole blood-cell cultures of Alzheimer’s patients compared to controls, which indicates an attenuated immune response. On the other hand, other studies have shown elevated levels of cytokines [69]. These studies may to be consistent with changes (in inflammatory phenotype) that are specific to certain disease stages as demonstrated by Sala et al. [70]. In fact, past and recent evidence suggests that peripheral modification of inflammatory factors may occur during the early development of AD [71,72]; these observations also reconcile epidemiological results that suggest that NSAIDs protect against AD [7380]. Furthermore, a meta-analysis of nine studies revealed that the benefit was greater with long-term treatment than with intermediate use [12]; however, NSAIDs do not have therapeutic effects and their use in AD may need to be initiated as early as possible to prevent disease progression [79,81,82].

Chemokines play an essential role in several physiological and pathological conditions, such as synaptic transmission and disease-associated neuroinflammation [83]. These molecules are small proteins that are able to induce a chemotactic response in cells expressing the corresponding chemokine receptors [84]. However, being molecules considered to exclusively coordinate immune cell migration, chemokines are at present considered versatile messengers which are able to coordinate the interaction between several cell types. Although neurons express and secrete chemokines, astrocytes and microglia are their primary source and Aβ-induced responses in microglial and astroglial cells is thought to produce a variety of neurotoxic substances, such as reactive oxygen and nitrogen species, pro-inflammatory cytokines, but also chemokines that cause neurodegenerative changes in Alzheimer’s [85,86]. Consequently, a well-controlled microglial activation that reduces microglial-mediated oxidative damage while promoting neuronal protection may be the key for Alzheimer’s therapy. Concurrently, microglial activation plays a role in amyloid removal, particularly compacted amyloid deposits - the critical neurotoxic components in Alzheimer’s brain - although this occurs at the expense of activated innate immunity that causes paracrine damage to neurons [87].

Activation of microglia and astrocytes and regional neuronal cell loss are observed in aging [61] [61] suggesting that neuroinflammation may play a pivotal role in early AD processes. Therefore, there is a strong consensus that any treatment which is able to promote the decrease of neuroinflammation is a therapeutic target for Alzheimer’s. However, several large epidemiological clinical trials - mostly using cyclooxygenase (COX)-2 inhibitors [14] or using multiple different NSAIDs - have failed to show any significant beneficial effects in AD patients with mild to severe cognitive impairment [88,89]. These results suggest, furthermore, that NSAIDs have a rather preventive than therapeutic effect and indicate that NSAIDs should be administered early before the onset of the symptoms and the treatment most likely has to become part of the daily life. The other possibility, not necessarily an alternative, points to the COX-1 inhibition, as a better therapeutic approach than selective targeting COX-2. COX-1 is responsible for the physiological production of prostanoids and COX-2 for the elevated production of prostanoids that occur in sites of disease and inflammation. Both COX-1 and COX-2, the constitutive and inducible forms of COX, respectively, are known to be involved in inflammatory responses and normal neuronal functions (Figure 6).

Figure 6.
Cyclooxygenase (COX) is the rate-limiting step in the production of prostaglandins (PGs) and is constitutively expressed throughout the normal brain [198,199]. The ability of aspirin (ASA) to modify COX-1 is the basis for the unique, long lived effect ...

Aspirin

Over 100 years ago ASA was made synthetically by Hoffman, a chemist working in a laboratory owned by Friedrich Bayer (Germany). The name, A-Spir-in is derived from A, as acetylated, and Spir, as Spiraea the Latin word for the original botanical name for meadowsweet, a plant which is rich in salicylates. Hoffman was motivated by his father’s severe arthritis who could not tolerate salicylic acid. Soon after ASA was widely accepted with great enthusiasm, and was very soon recommended in the medical press for several uses such as fever, migraine, pain, rheumatoid arthritis (http://www.aspirin-foundation.com/about/about.html). ASA is by far the most widely studied and researched drug. In the last century, ASA has become very popular. Firstly, ASA was used during the Spanish flu pandemic (1918–20) for its analgesic and antipyretic properties. Since the 70s - when ASA was shown to be an anti-thrombotic agent [90] - low-dose ASA has been routinely used for the prevention of secondary ischaemic cardiovascular events, although some studies have suggested that this is associated with an increased risk of haemorrhagic stroke. A meta-analysis published in 1998 has quantified this risk [91] and has concluded that, although there is a slight increase in the risk of haemorrhagic stroke in patients treated with ASA, this is outweighed by the reduction in the risk of ischaemic strokes, which are far more numerous, and in the reduction in the risk of other ischaemic cardiovascular events. Hence, current European and American guidelines guarantee that ASA is clearly recommended as an antiplatelet agent for secondary prevention in the reduction of cardiovascular events [92,93]. Even at very low doses, a lasting inhibition of platelet COX-1 activity blocks thromboxanes (TX)A2, which is an important physiological activator of platelet aggregation [94,95]. Consequently, irreversible inhibition of platelet COX-1 by ASA may lead to the prevention of arterial thrombosis as well as bleeding complications [96,97] even at the most commonly low doses used (75 to 100 mg) to provide antiplatelet activity [98,99]. Therefore, a recent meta-analysis suggests that the use of ASA for primary prevention significantly reduces the incidence of some cardiovascular events but results in no significant reduction in overall mortality [96]. The inhibition of TXA -mediated platelet aggregation, is independent of a dose in excess of 30 mg daily [95].

The best-characterized action mechanism of ASA occurs through inhibition of the activity of COX-1 and COX-2 enzymes. Both prostaglandin H synthases (here referred to as COX-1 and COX-2) are homodimers, but the monomers often behave asymmetrically as conformational heterodimers during catalysis and inhibition. ASA maximally acetylates one monomer of human COX-2 (Figure 6). The acetylated monomer of ASA-treated (AT) COX-2 maintains its hydroperoxide activity - and, for example, generates 15-hydroperoxyeicosatetraenoic acid from AA - while the non-acetylated, partner monomer forms mainly PGH2, although only at a reduced rate of native enzyme. Conversely, ASA acetylates one monomer of COX-1 with following inhibition loss of COX activity. Thus, the effect of ASA on COX-2 is an incomplete allosteric inhibition effect compared to that seen with COX-1. However – due to this allosteric mechanism - the history of ASA seems not to be concluded and there are chances that ASA will reinforce its success in the present century, by contributing in the primary prevention of AD. If ASA offers a new perspective in the prevention of dementia of Alzheimer’s type, this action will be not restricted to ASA alone, but will take place only with the simultaneous intake of DHA.

DHA and Alzheimer’s

DHA is a major constituent of neuronal membranes and, along with other long-chain n3 PUFAs from fish (g.e., eicosapentaentoic acid, EPA), has a wide variety of beneficial effects on neuronal functioning, inflammation, oxidation and cell death, as well as on the development of the characteristic pathology of AD (Figure 7). DHA may modulate a number of cellular processes in the brain and may regulate from the diet both prostaglandin and pro-inflammatory cytokine production [100]. This could explain the protective role of n3 PUFAs in neurodegenerative diseases linked to aging. The above results are in agreement with the observations that greater consumption of fish (rich in DHA) significantly reduced the likelihood of developing AD [101,102] and that 900 mg/d of DHA may provide neuroprotection in very early cognitive deficits [103]. Such cognitive changes likely occur as a consequence of normal aging or may be observed before a diagnosis of MCI or mild AD. These results suggest that DHA may play a role in the disease [104]. Alzheimer’s seems to involve disturbed DHA metabolism and decreased DHA serum content correlates with cognitive impairment [105]; moreover, DHA - which is concentrated in membrane phospholipids at synapses - is decreased in AD brain [106] and reduced serum levels of DHA have been linked to an increased risk of AD in epidemiological studies [107].

Figure 7.
Anti-inflammatory effects of docosahexaenoic acid (DHA) may result, at least in part, from the inhibitory effects performed by DHA and DHA-derived docosanoids (i.e., neuroprotectin D1, NPD1) [201205]. Brain synaptic terminals and neuronal plasma ...

The DHA deficiency may be due to enhanced free radical-mediated lipid peroxidation [108], decreased dietary intake and/or impaired liver DHA being delivered to the brain. Thus, DHA supply to the brain is necessary not only for cell development and function, but also to restore membrane phospholipids that may decrease as a consequence of lipid peroxidation (also nonenzymatic peroxidation, i.e., neuroprostanes [109]), as it particularly occurs in aging and neurodegeneration such as AD. Furthermore, as it has been already been shown for NSAIDs, randomized trials of DHA supplementation have found positive effects on some aspects of cognition in older adults who were cognitively healthy or had mild cognitive impairment, although, even recently, little effect was found in participants with AD [110].

Schaefer and his colleagues [102] reported that men and women in the quartile with the highest DHA intake levels, compared with subjects in the lower 3 quartiles, had a relative risk of 0.53 of developing all-cause dementia and 0.61 of developing AD. This study has been the first to link blood levels of DHA to protection against AD and, at the same time, is indicative of a general healthy effect of DHA on the aged brain. Specifically, growing evidence suggests that the presence of DHA promotes growth of hippocampal neurons [111] and stimulates neurite growth [112]. DHA supplementation enhances endothelium-dependent vasodilatation and artery blood flow protects the circulatory system [113] by acting on cerebral microcirculatory abnormalities that can cause atrophy of the synaptic termini leading to the synaptic loss described in AD brains. There is now sufficient evidence that Aβ peptides do not affect neuronal viability in general, but they interfere in particular with synaptic function and they eventually cause the degeneration of synapses, which becomes most apparent on a morphological level by retraction of dendritic spines [114]; DHA attenuates Aβ secretion [115], thus protecting synapses (Figure 7). Some NSAIDs (i.e., ibuprofen, indomethacin, and naproxen), but not all (i.e., ASA), have been shown to be able to activate peroxisome proliferator-activated receptor gamma (PPARγ) [116]. PPARγ depletion potentiates β-secretase [β-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels [117]; on the other hand, overexpression of PPARγ, as well as NSAIDs and PPARγ activators, reduced BACE1 gene promoter activity.

Moreover, PPARγ mitigates inflammation after ischemic stroke [118]. Since inflammation is commonly recognized as a process which causes secondary brain damage [119], the anti-inflammatory effect of PPARγ agonists results as a key mechanism for the beneficial role of PPARγ. In addition to its anti-inflammatory effect, PPARγ regulates the expression of some important antioxidative enzymes such as catalase, SOD1, and GST [120122] that could effectively ameliorate oxidative stress.

Interestingly, Guillot et al. [123] have recently demonstrated that DHA increases PPARγ mRNA.

The phosphatidylinositol 3-kinase [PI (3)K]/Akt signaling is a critical mechanism in neuronal survival [124], and its regulation by external stimuli has been well documented [125]. DHA promotes neuronal survival by facilitating membrane translocation/activation of Akt through its capacity to increase phosphatidylserine (PS), the major acidic phospholipid in cell membranes [126].

Finally, DHA blocks the signaling cascade between Toll-like/cytokine receptors and the activation of NF-κB [127]. Toll-like receptors (TLRs) are transmembrane receptors that initiate signals in response to diverse stimuli, including infection and tissue injury. It is now recognized that the lipid components of the diet can modulate transmembrane TLRs and the consequent inflammatory and immune responses. TLRs are expressed in a variety of mammalian immune-related cell types and are also present in microglia [128], astrocytes [129], oligodendrocytes [130], and neurons [131. Recent, cumulative evidence suggests that TLRs take part in making possible neurodegenerative conditions.

Production and effects of Neuroprotectin D1

DHA has been implicated in memory and neuroprotection. Specifically, oxidative stress strongly enhances free DHA accumulation as a function of time stress [132]. Free DHA released in the brain during experimental stroke leads to the synthesis of messengers through oxygenation pathways. The first evidence for the central nervous system conversion of DHA to mono-, di- and tri-DHA-derived products, was obtained from the retina in1984 [133]. Enzymatic inhibition has suggested a role for lipoxygenase in the biosynthesis of these hydroxy-DHA mediators (Figure 8). The initial step in the bioactive pathways is the release of DHA from phospholipid membrane by phospholipase/s A2. This hydrolysis may be stimulated by cytokines, for example, IL-1β. Among these new DHA-derived molecules, attention has been focused on a new specific hydroxyl fatty acid, called neuroprotectin D1 (NPD1). The name ‘neuroprotectin’ was suggested according to its neuroprotective bioactivity in oxidative stressed retinal pigment epithelial cells [134] and the brain [135]; ‘D1’ because it is the first identified neuroprotective mediator of DHA.

Figure 8.
Neuroprotection and biosynthetic pathways for aspirin (ASA)-triggered Lipoxins, Resolvins, Protectins and electrophilic oxo-derivatives (EFOXs) [17,166,168, 207]. ASA enables the biosynthesis of these mediators by catalitically switching cyclooxygenase ...

NPD1 potently inhibits events that trigger DNA fragmentation and CNS apoptosis [134]. The discovery that NPD1 is a bioactive mediator of DHA has shed additional light on the biological importance of this n3 fatty acid. Pro-inflammatory gene expression profiles in human brain cells in culture – on exposure to Aβ, DHA, and nNPD1- show that inducible pro-inflammatory cytokines expression is up-regulated by Aβ and down-regulated by DHA or NPD1 [136]. This action of both NPD1 and DHA may represent a cytoprotective response of brain cells when confronted with a peptide that triggers oxidative stress. In particular, NPD1 (50 nM) protects both neurons and glia from Aβ-directed apoptosis [136] and it up-regulates the antiapoptotic genes encoding Bcl-2, Bcl-xl, and Bfl-1(A1) in human brain cells in culture [137]. Interestingly, in human neural cells, while attenuating Aβ secretion, DHA promotes the concomitant formation of NPD1, whose level is particularly reduced in the hippocampal region from Alzheimer’s patients [136]. Generation of NPD1 from DHA therefore appears to redirect cellular life toward successful preservation of brain cells.

Towards an approach for prevention of AD

The above observations suggest potential evidence linking neuroinflammation and endothelial dysfunction with cognitive deficit and, ultimately, with AD; moreover, retrospective epidemiological studies indicate that chronic, long-term treatment with NSAIDs decreases the risk of developing AD. These results suggest, once more, that neuroinflammation may play a pivotal role in early disease processes. NSAIDs may act via several pathways to influence AD pathogenesis. Firstly, NSAIDs can reduce neuroinflammation via canonical anti-inflammatory pathways within the brain. Secondly, NSAIDs can act as γ-secretase (a multi-subunit enzyme complex that plays a pivotal role in the generation of Aβ from its parent molecule, the amyloid precursor protein, (APP)) modulators [138]. An acute administration of selective NSAIDs results in the production of shorter, less amyloidogenic Aβ peptides both in vitro and in vivo most likely through interactions with APP that influence γ-secretase cleavage. Thirdly, NSAIDs may also regulate the levels of β-secretase (the enzyme responsible for initiating Aβ generation) through a PPARγ-mediated pathway [117]. Finally, NSAIDs may act to inhibit the formation of Aβ oligomers and deposits through direct interaction with the Aβ peptide [117]. However, despite many proposals for alternative actions of NSAIDs in AD, no data demonstrate major preventive action in vivo other than through COX action.

Specifically, and for reasons that will be clear later, this review focuses on aspirin (ASA), and its use in primary, or secondary, prevention of AD. Prevention seems to be the only possibility as there is no definitive treatment for the disease. The impossibility to cure Alzheimer’s patients also applies to ASA, as it has been well documented in the randomized open-label trial reported by AD2000 Collaborative Group, that concluded “Although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose ASA has no worthwhile benefit and increases the risk of serious bleeds.” [139]. However, the AD2000 also reported “A larger benefit might occur after several years of aspirin treatment, … beyond 2 years.” Thus, it seems that ASA long-term treatment and follow-up, would be needed to establish that ASA has no efficacy in AD. Nonetheless, it is possible that in that study the limited benefit of ASA was caused by the absence of DHA.

The approach that is indicated in this review is the coupling of ASA (low doses ≤ 30mg, presumably with a lower risk of gastrointestinal bleeding than with higher doses of ASA) and the n3 PUFA DHA. There is more than one reason to privilege DHA; for example, DHA - together with arachidonic acid (AA) - make up about 20% of FAs in the mammalian brain [140] and may produce effective neuroprotection in presence of ASA [135,141]. Moreover, Alzheimer’s seems to involve disturbed DHA metabolism [101,102,110,142144]. Additional reasons are that DHA is : a) concentrated in the synaptic membrane and its level is dependent on liver processing of the dietary DHA or of its precursors, followed by blood lipoprotein transport; b) involved in memory formation [145]; c) involved in excitable membrane function [146]; d) involved in neuronal signaling [147]; e) implicated in neuroprotection [148,149]; f) the precursor of lipid mediators (e.g., neuroprotectin and resolvins (Figure 8)) that counteract pro-inflammatory, cell-damaging events triggered by multiple, converging cytokine and, in the case of Alzheimer’s, amyloid peptide factors [18].

The source of inflammatory processes in the brain is usually sought among the peripheral inflammatory cells, which may invade the brain, and in activated glia [150,151]. Peripheral pro-inflammatory cytokines - in particular IL1β, TNFα, and, to a lesser extent, IL6 - may produce strong effect on the brain [152154]; these molecules activate microglia and produce inflammatory mediators affecting neuronal functioning, thus causing a short-term alteration in normal cognitive function [155]. A number of mechanisms - which work concurrently and are triggered by an original peripheral cytokine signal - can be transmitted to the brain. Cytokines can enter the brain either by volume diffusion [156] or through cytokine transporters at the BBB [157], or enter via the circumventricular region, where the BBB is irregular [158]. Moreover, cytokine receptors - located on perivascular macrophages and brain endothelial cells - may be activated by circulating cytokines with the subsequent local production of COX-2-derived main product PGE2 [159,160], which stimulates the production of Aβ and, consequently, the inflammation-mediated progression of AD [161].

(ASA + DHA) ACTION

It is now clear from numerous studies that ASA has beneficial effects in common and beyond other NSAIDs [162,163]. Recent studies discussed the potential preventive actions of n3 PUFA supplementation, particularly DHA, in Alzheimer’s [101103, 142,164]. Considering the similar favourable profiles attributed to dietary DHA and to ASA in primary prevention of AD, is there any evidence for possible synergistic effects due to the concomitant presence of ASA? Moreover - as knowledge that unresolved inflammation is important in many neurodegenerative diseases including AD [165] - could DHA utilization during ASA therapy produce neuroprotective bioactive molecules?

Serhan’s group [166] has answered these questions. ASA irreversibly acetylates COX-2 and - in presence of DHA - changes the enzyme’s products from intermediates for PGs and TX to precursors for NPD1 and resolvins [167,168]

The COX-2-ASA-dependent conversion of DHA is likely to be elevated in Alzheimer’s where COX-2 is upregulated [169] and thus, if these mediators have a neuroprotective action, DHA and ASA may protect the brain, particularly in the elderly.

DHA and its oxygenated derivative NPD1 show strong anti-inflammatory effects [170], in addition to a reduction of Aβ production and deposition [171]. Furthermore, it should be convenient to experiment if the association ASA-DHA could result in delaying AD. The new series of endogenous mediators have been designed as DHA-derived aspirin-triggered resolvins (AT-RvD) and neuroprotectin D1 (AT-NPD1). These oxygenated DHA derivatives have been added to the previous families of potent DHA-derived messengers, RvD and NPD1 discovered by Bazan et al. [132]. In particular, all these molecules are generated locally in response to inflammatory stimuli, and they have potent anti-inflammatory action. Moreover, they significantly reduce polymorphonuclear cells infiltration in vivo as effectively as equivalent doses of indomethacin, although they are subject to inactivation by further oxydation; however, it is important to note that AT-derivatives are more resistant to the enzyme oxidation [172], and thus are expected to exert a better neuroprotection than the original product discovered by Bazan et al. [132]. In conclusion, as AT-derivatives resist rapid inactivation, ASA-triggered forms may contribute to a new, potent neuroprotection action of ASA and DHA in the human brain. On the whole, these observations pave innovative ways to therapeutic exploration, mainly, in AD.

Conclusion

COX-1 and COX-2 are targets of ASA and other NSAIDs. For example, ASA acts via COX-1 to inhibit platelet TXA2 formation and as a clinical consequence lowers the relative risk for mortality from cardiovascular disease [94]. COX-2 is the appropriate target of NSAIDs acting to inhibit inflammation. Low doses of ASA irreversibly inhibits COX-1, but only modifies the enzymatic activity of COX-2.

ASA is a non-selective COX-2 allosteric effector which acetylates COX- 2 at low-doses. The acetylated COX-2 enzyme also slows the prostanoid generation [173]. DHA-derived molecules generated from human activated microglial cells - via ASA-acetylated COX-2 - inhibit cytokine generation in the picomolar range thus eliciting neuroprotection [166,174]. Therefore, although a very large trial of ASA and DHA, with long-term treatment and follow-up, would be needed to establish that this treatment has some efficacy in AD, our hypothesis is encouraging to undertake such a study - particularly with very low-dose ASA (≤ 30 mg/day, in vivo). In conclusion, despite the evidence of epidemiological studies with ASA, various lines of research suggest that the concomitant presence of DHA and ASA may indeed provide multiple levels of protection against the course of Alzheimer’s.

The uncommon ASA-COX-2-DHA pathway has been, very recently, reinforced, by the discovery of the COX-2-derived 17-hydroxy-DHA molecule produced by activated macrophages in the presence of ASA [17]; this new mediator - designed as electrophilic oxo-derivative (EFOX) (Figure 8) - modulates the pro-inflammatory NF-κB pathway and activates PPARγ, implying that this oxo-DHA molecule may mediate anti-inflammatory and metabolic signaling through PPARγ-regulated gene expression [175].

In conclusion, it may be hypothesized that both DHA and its AT-derived lipids (resolvins, neuroprotectins and EFOX) will be the culprit of many literature data. Parmacology (very low doses ASA) and diet (fish and DHA) may be helpful in reducing the risk for AD, although large randomized clinical trials are warranted to further explore the relationship between (DHA+ASA) supplementation and dementia.

Acknowledgments

This work was supported by the National Ministero dell’Istruzione, dell’Università e della Ricerca. (MIUR).

Footnotes

Conflict of interest

The other authors declare no conflict of interest.

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