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Biochim Biophys Acta. Author manuscript; available in PMC Aug 1, 2011.
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PMCID: PMC3024142

Phospholipase A2 and Arachidonic Acid in Alzheimer’s Disease


Essential fatty acids (EFA) play a critical role in the brain and regulate many of the processes altered in Alzheimer’s disease (AD). Technical advances are allowing for the dissection of complex lipid pathways in normal and diseased states. Arachidonic acid (AA) and specific isoforms of phospholipase A2 (PLA2) appear to play critical mediator roles in amyloid-β (Aβ) - induced pathogenesis, leading to learning, memory, and behavioral impairments in mouse models of AD. These findings and ongoing research into lipid biology in AD and related disorders promise to reveal new pharmacological targets that may lead to better treatments for these devastating conditions.

Essential Fatty Acids and Phospholipase A2

Essential fatty acids comprise a subset of unsaturated fatty acids that play critical roles in normal neuronal and glial physiology by regulating intracellular signaling and membrane function. Humans rely on dietary intake of EFAs because they lack the necessary enzymes to synthesize them. EFAs are packaged into hepatic lipoproteins before transport to the brain where they are incorporated into phospholipids (PLs). EFAs can be released from the sn-2 position of PLs by phospholipase A2. Liberated EFAs and their metabolic products modulate synaptic function, neuronal toxicity, cerebrovascular tone, neuroinflammation, amyloid precursor protein (APP) processing, and oxidative stress [1, 2].

EFAs can be subdivided into omega-3 and omega-6 subgroups, depending on the distance between the end of the fatty acid chain and the nearest double bond. The principal omega-3 fatty acids are α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The principal omega-6 fatty acids are linoleic acid (LA) and AA (Figure 1). In the brain, AA and DHA appear to be the most important. DHA and AA are enriched in brain PLs, make up the majority of free fatty acids and appear to be the most biologically active [1, 3].

Figure 1
PLA2-dependent fatty acid metabolism. PLA2 mediates the release of fatty acids from membrane phospholipids (PL), including linoleic acid (LA), α-linolenic acid (ALA), arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid ...

PLA2s make up a growing family of lipases that are categorized into 12 groups and vary by biological activity, substrate specificity, activating factors and localization [4, 5]. In the CNS, Groups IIA, IVA, V and VI have been studied the most [6, 7]. GIVA-PLA2 has the strongest substrate specificity for AA [5], is expressed constitutively in neurons [3, 8, 9] and can be induced in glia [10]. PLA2 activity is particularly high in the hippocampus, consistent with the high levels of GIVA-PLA2 protein in hippocampal neurons [3]. However, in the brain, GIVA-PLA2 is also present in endothelial cells, vascular smooth muscle cells and hematopoietic cells [11, 12]. GIVA-PLA2 is primarily regulated by intracellular Ca2+ concentrations and by phosphorylation at several sites that control its translocation to and interaction with its PL substrate [5]. The phosphorylation sites are regulated primarily by mitogen-activated protein (MAP) kinases [5]. Free AA levels in the brain are probably determined mostly by GIVA-PLA2 activity, although AA may also be generated as a byproduct of endocannabinoid hydrolysis by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)[13].

GVIA-PLA2 is expressed in diverse cell types and brain regions [14] and, in contrast to GIVA-PLA2, does not require Ca2+ for activation. Although it does not have a preference for any particular fatty acid substrate [4], it is the predominant PLA2 responsible for DHA release in the brain [7]. Other isoforms, such as GIIA and GV, are also expressed in the brain, but less is known about their function [6].

Physiologic Roles of AA and PLA2 in Regulation of Neuronal Activity

A number of findings suggest that PLA2 and AA play important roles in synaptic signaling, long-term potentiation (LTP), learning and memory. Non-specific pharmacologic inhibition of PLA2 activity in rats impaired performance during the probe trial portion of the Morris water maze [15]. Similarly, non-specific inhibition of PLA2 activity diminished memory retrieval after avoidance training [16, 17]. Inhibitors with a preference for GVIA-PLA2 impaired performance on Y-maze testing [18]. In contrast, specific reduction of GIVA-PLA2 by genetic modulation had no negative impact on learning and memory measured in the Morris water maze [3]. Further studies are required to determine what roles GIVA-, GVIA-, and other PLA2 isoforms play in behavioral functions and the specific mechanisms involved.

The effect of PLA2s on cognitive function may relate, at least in part, to the ability of AA to alter neuronal and synaptic activity. AA can increase neuronal firing [3, 19] and enhance LTP in hippocampal neurons in anesthetized rats and hippocampal slices [20]. How AA enhances synaptic transmission and LTP is not completely understood. AA rapidly increases the level of α-amino-3-hydroxy-5-methyl-4-isoxazaolepropionic acid receptors (AMPARs) at the neuronal surface [3], which might increase neuronal activity by increasing currents through Ca2+-permeable AMPARs [21] and N-methyl-D-aspartic acid receptors (NMDARs) [22]. Therefore, AA may mediate changes in AMPAR surface levels. AMPA binding in hippocampal slices was increased by exogenous PLA2, possibly by increasing AA-mediated increase in surface AMPAR levels [23]. The opposite was observed with PLA2 inhibition [24]. By regulating surface levels of AMPARs [3] and NMDARs (Cisse and Mucke, unpublished data), PLA2 and AA may potentiate LTP, learning and memory. Consistent with this idea, LTP can be blocked with PLA2 inhibitors, and this blockade can be reversed by the addition of exogenous AA [25]. Notably, these findings do not preclude the possibility that excessive levels of PLA2 and AA in disease states could have detrimental consequences (see below) [1, 3, 26].

Indeed, the ability of AA to increase neuronal activity could escalate to abnormal levels through several positive feedback mechanisms. Increasing neuronal activity by electrical stimulation in the dentate gyrus increases PLA2 activity and AA liberation [27]. Similarly, neuronal activation with glutamate generates a Ca2+-dependent increase in PLA2 activity and AA levels that depends on NMDARs and AMPARs [28]. NMDA treatment can increase AA production [29, 30], and kainate can increase neuronal GIVA-PLA2 protein levels in the hippocampus [8]. Lastly, neuronal activity increases the production and release of Aβ [31], which should increase GIVA-PLA2 and AA [3, 26].

AA may affect neuronal functions directly or indirectly through one of its many metabolites (Figure 1). Prostaglandins (PGs) are formed by cyclooxygenase (COX)-dependent metabolism of AA. COX, like GIVA-PLA2, is concentrated in the hippocampus, particularly in dendritic spines [32]. COX inhibition diminishes LTP induction [33] as well as spatial learning in the water maze [34]. AA can also be metabolized by the lipoxygenase pathway to generate hydroxyeicosatetraenoic acid (HETE) and leukotrienes (LTs), which have also been shown to regulate synaptic function. Lipoxygenase inhibitors block hippocampal LTP [35], and 12-HPETE can induce long term depression (LTD) in CA1 pyramidal cells in hippocampal slices [36].

DHA is liberated in the brain predominantly by GVI-PLA2 [7] and possibly plasmalogen-selective PLA2 (PlsEtn-PLA2) [12]. There is less evidence to support a direct link between DHA and synaptic function, but DHA is important for neuronal survival and development [37], promotes neurite outgrowth in the hippocampus [38], and may affect neural transmission by affecting membrane fluidity [37]. Further, DHA and AA compete for phospholipid binding sites and increases in dietary DHA intake decreases levels of phospholipid-bound AA that is available for release by PLA2 [39]. Neuronal activity is tightly linked to the availability of oxygen and nutrients through the neurovascular unit [4042]. Increase in neuronal activity must be matched by cerebrovascular dilation in order to calibrate blood flow to energy needs. GIVA-PLA2 and AA metabolites play an important role in regulating cerebrovascular tone in response to neuronal activity [12]. PGs (PGD2, PGE2, PGI2) and epoxyeicosatrienoic acids (EETs) mediate arterial vasodilation, increasing cerebral blood flow (CBF), whereas PGs (PGF2a and TXA2) and LTs (LTC4, LTD4, LTE4) mediate vasoconstriction [11, 12]. Therefore, AA metabolites can regulate not only neuronal activity, but also associated changes in cerebrovascular tone.

Altered AA Metabolism in hAPP mice

Fatty acid metabolism is a dynamic process determined by the availability of substrate, enzymatic activity, and access of the enzyme to the substrate (Figure 1). Alterations in the levels of individual fatty acids or enzymatic activities can affect the concentration of multiple other metabolites. Therefore information on multiple metabolites in a pathway is more informative than data on select mediators. However, measurement of multiple fatty acids simultaneously was not practical until the recent introduction of multiple chromatography and mass spectrometry techniques [43]. These new techniques allow for a snapshot of fatty acid metabolism in an unbiased manner to assess the consequences of experimental perturbations and disease states [3, 4446]. We recently used liquid chromatography coupled with tandem mass spectrometry to analyze fatty acid metabolism in human amyloid precursor protein (hAPP) transgenic mice (line J20), which simulate key aspects of Alzheimer’s disease (AD). This analysis revealed an increase in free fatty acid liberation in the hippocampus of these mice, as compared with nontransgenic (NTG) controls [3]. The increase was largely due to a specific elevation in the production and metabolism of AA [3]. Because this alteration was not seen in transgenic mice overexpressing wildtype hAPP, it was probably caused by increased Aβ levels or another consequence of the FAD mutations expressed in the hAPP-J20 line [3].

In addition to elevations in AA, hAPP-J20 mice showed an increase in COX-dependent metabolites such as PGs [3]. This increase in PGs may be due to an increased supply of AA to COX or to increases in the activity of the inducible isoform of COX, COX-2. AA released by GIVA-PLA2 can increase COX-2 transcription leading to increased protein levels [47]. This causal chain may also explain the elevated levels of COX-2 seen in response to Aβ in vitro [2, 48], in AD patients [4951] and in hAPP mice [52]. The increase in AA and PGE2 in hAPP mice could increase neuronal activity and lead to excitotoxicity, which may play an important role in the pathogenesis of AD [5356].

The increase in PGD2, PGE2 and EETs in hAPP mice could also promote cerebrovascular dilation, which may represent a physiological response to increased neuronal activity or a compensatory response to the vasoconstrictive effects of Aβ [5760]. How Aβ causes vasoconstriction is unknown [57].

Some of the fatty acid metabolites that are increased in hAPP mice (e.g., AA, PGE2, and LTB4) have proinflammatory activities and could be related to neuroinflammatory processes seen in AD [6163]. Elevations in AA might also contribute to oxidative stress, because AA metabolism generates reactive oxygen species as a byproduct [64]. Indeed, markers of oxidative stress are increased in AD brains and in some lines of hAPP mice [6567]. Isoprostanes, non-enzymatic oxidation products of AA, are released from PLs by PLA2. Therefore, the increased activity of PLA2 would be expected to result in increased release of isoprostanes, whose levels are elevated in AD patients and hAPP mice [65, 68]. Another non-enzymatic product of AA oxidation, 4-hydroxynonenal (4-HNE), is also elevated in AD [69]. An increase in AA release from PLs should decrease levels of PL-bound AA, and this alteration is indeed seen in AD patients as compared to non-demented controls [70].

Increased Activation of GIVA-PLA2 in hAPP mice and AD

Consistent with the selective increase in AA and its metabolites in the hippocampus of hAPP mice, these mice had increased levels of activated GIVA-PLA2 in the hippocampus, where GIVA-PLA2 immunoreactivity was highest in neurons of CA1-3 regions and dentate gyrus [3]. GIVA-PLA2 is activated by phosphorylation at several sites. ERK and p38 MAPK phosphorylate Ser505, whereas Ca2+/calmodulin-dependent kinase (CaMK)II phosphorylates Ser515 and MAPK interacting kinase (MNK)1 phosphorylates Ser727 [5, 6]. GIVA-PLA2 can also be phosphorylated by protein kinase C (PKC)-dependent kinases [71]. Phosphorylation of Ser505 appears to be most important for regulating GIVA-PLA2 activity [5], and Aβ increased phosphorylation of this residue in both neuronal culture and hAPP mice [3]. Phosphorylation of Ser505 was also increased in the hippocampus of AD patients, as compared to non-demented controls and patients with frontotemporal dementia [3]. Increased phosphorylation of this residue suggests increased activation of MAPK. Indeed, inhibition of MAPK blocked Aβ-mediated GIVA-PLA2 phosphorylation in neuronal cultures [3], establishing a new role for the MAPK pathway in AD [72, 73].

GIVA-PLA2 activity is also regulated directly by intracellular Ca2+ concentrations. The C2 domain of GIVA-PLA2 binds Ca2+ allowing GIVA-PLA2 to translocate to the Golgi apparatus, endoplasmic reticulum and nuclear envelope, where it gains access to PL-bound AA [5, 6]. Several processes may increase intracellular Ca2+ levels in AD [55], which would be expected to increase GIVA-PLA2 activity. GIVA-PLA2 activity can also be increased by transforming growth factor (TGF)-β [74], whose production by cultured primary cortical neurons is increased by Aβ and whose levels are elevated in brains of AD patients and hAPP mice [7577].

GIVA-PLA2 activity was not increased in mice overexpressing wildtype hAPP, which have much lower levels of Aβ than hAPP mice expressing FAD-mutant hAPP[3]. In cultured neurons, Aβ treatment increased GIVA-PLA2 activation in a dose-dependent manner[3]. These findings suggest that Aβ causes GIVA-PLA2 activation in hAPP mice and in AD. Elevations in GIVA-PLA2 activation and AA metabolism are also seen in other neurological conditions where Aβ is elevated such as stroke and traumatic brain injury[1, 7882].

AA May Mediate Aβ-Induced Excitotoxicity

Aβ can increase neuronal activity and cause excitotoxic injury [55, 8385]. Because Aβ increases the activation of GIVA-PLA2, which liberates AA from PLs, AA may be a key mediator of these effects [3, 8588]. Indeed, AA itself is excitotoxic [1, 3, 89] and pharmacological inhibition of GIVA-PLA2 prevented Aβ from increasing neuronal activity in cortical slices and from eliciting neuronal degeneration in cell culture [3]. Interestingly, Aβ and AA acutely and transiently increased the level of AMPARs on the neuronal surface [3]. This effect could account, at least in part, for their detrimental effects, as excesses in AMPAR-mediated neuronal activation can lead to excitotoxicity [55, 8385, 90].

A transient elevation in surface AMPARs would enhance NMDAR activation, Ca2+ influx and membrane depolarization. The transient increase in intracellular Ca2+ would also be expected to further activate GIVA-PLA2 and increase AA release. AA and its metabolites are diffusible and, thus, could affect the function of surrounding neurons. This scenario is particularly interesting in light of evidence for epileptiform activity in hAPP mice and patients with AD [53, 91, 92].

GIVA-PLA2 Mediates Aβ-induced Behavioral Deficits in hAPP Mice

Like humans with AD, hAPP mice develop a range of behavioral alterations, including deficits in learning and memory. Interestingly, behavioral deficits in hAPP-J20 mice depend, at least in part, on GIVA-PLA2 [3]. On the GIVA-PLA2 wildtype background, hAPP-J20 mice show deficits in hippocampus-dependent learning and memory. These mice also have increased hippocampal levels of GIVA-PLA2 activation, as do patients with AD [3]. What is more, genetic ablation of GIVA- PLA2 in hAPP mice reduced their learning and memory deficits [3].

hAPP mice also have other behavioral alterations such as disinhibition and hyperactivity that may be related to problems with encoding new information [93] . Reduction or removal of GIVA-PLA2 also improved these behavioral deficits. Furthermore, hAPP mice suffer from premature mortality, which may be due to epileptic activity [54, 91, 92]. Decreasing GIVA-PLA2 in hAPP mice would be expected to decrease Aβ-induced neuronal excitation and raise the seizure threshold, thereby lowering mortality. Indeed, reduction or removal of GIVA-PLA2 reduced premature mortality in these mice [3].

Learning and memory deficits in hAPP-J20 mice correlate with depletions in specific synaptic activity-related markers, such as calbindin [94, 95]. Interestingly, removal of GIVA-PLA2 in hAPP-J20 mice restores normal calbindin levels. GIVA-PLA2 inhibition therefore ameliorates both behavioral and biochemical Aβ-induced deficits in hAPP-J20 mice. Most likely, GIVA-PLA2 mediates these effects through previously unknown mechanisms that affect neuronal excitation and network activity.

The striking effects of GIVA-PLA2 modulation in hAPP mice raise the possibility that it may play an important role in the pathogenesis of AD-related cognitive and behavioral abnormalities and call attention to its potential value as a therapeutic target in this disease.

Therapeutic Targets and Drug Development

As outlined above, PLA2s fulfill important physiological functions, but some of them are also involved in pathogenic pathways, making the development of isoform-specific inhibitors an important therapeutic objective. In relation to AD, specific inhibition of GIVA-PLA2 may be desirable based on the data reviewed here. However, it has been difficult to develop selective inhibitors for specific PLA2 isoforms. Many inhibitors initially thought to be specific were later shown to inhibit also other isoforms. For example, AA-trifluoromethylketone (AACOCF3) has a strong preference for GIVA-PLA2 over other PLA2 isoforms but also inhibits GVIA-PLA2, thromboxane synthase and FAAH. Therefore, studies evaluating the in vivo role of GIVA-PLA2 have used genetic ablation instead of pharmacologic inhibition [3].

New GIVA-PLA2 inhibitors are being introduced, although it is unclear if further scrutiny will confirm their reported specificities [96]. Wyeth (now Pfizer) has developed indole-based inhibitors that are reported to be highly specific for GIVA-PLA2. One of these inhibitors, WAT0196025, blocks GIVA-PLA2 but not the GIVB or GIVC isoforms. This inhibitor prevented the development of experimental autoimmune encephaomyelitis (EAE) [97]. Merck has introduced heteroaryl-substituted acetone derivatives that inhibit GIV-PLA2s at micromolar concentrations [96]. Others have developed similar compounds that inhibit GIVA-PLA2 at nanomolar concentrations [96]. 2-oxoamide inhibitors of GIVA-PLA2 based on γ-amino acids have also been developed and are undergoing testing [96].

Another strategy to decrease GIVA-PLA2-dependent AA production is to decrease the availability of PL-bound AA by displacing AA with DHA [37, 98]. Indeed, observational studies suggest the beneficial effects of increasing omega-3 dietary intake in mild cognitive impairment (MCI) and AD patients are due to increasing DHA and lowering AA [37] The MIDAS [99] and ADCS DHA [100] trials did not show a benefit of DHA treatment in mild to moderate AD patients but improved cognitive performance in individuals without AD who presented with memory complaints, suggesting the potential need for earlier intervention. Other studies have related a high omega-3 to omega-6 fatty acid ratio in the blood to a lower incidence of AD or cognitive decline independent of AD [37]. Other potential benefits of DHA include its abilities to block the Aβ-induced loss of NMDARs [98], decrease Aβ production, inhibit apoptosis, increase brain-derived neurotrophic factor (BDNF), serve as an anti-oxidant, increase neuroprotectin D1, and improve coupling of blood flow to glucose utilization [37].

Lastly, specific downstream effects of AA may be blocked by inhibiting distal AA processing enzymes. Epidemiological studies have linked the intake of non-steroidal anti-inflammatory drugs (NSAIDs) to decreased risk of developing AD[101]. Although animal studies support this notion [102], a prospective, randomized clinical trial did not show benefits of COX inhibition in AD [101, 103]. However, the trial evaluated only one year of treatment with rofecoxib or naproxen in patients with established mild to moderate AD [103]. It is noteworthy in this context that inhibition of distal enzymes in the AA pathway can divert proximal substrates to other enzymes. For example, in some patients, COX inhibition can lead to shunting of AA into the lipoxygenase pathway with secondary bronchospasm or allergic skin reactions [104]. In AD, COX inhibition could exacerbate the increase in AA levels that results from Aβ-induced GIVA-PLA2 activation, which in turn might offset downstream benefits of COX inhibition. Inhibitors of GIVA-PLA2 could avoid this problem.


The role of essential fatty acids in the pathogenesis of AD is intriguing. While studies have so far failed to demonstrate a clear benefit of DHA and of inhibiting COX, AA and GIVA-PLA2 represent new targets that appear to play important roles in mediating biochemical and cognitive abnormalities caused by Aβ. AA and its metabolites regulate many of pathways that are altered in AD, further underlining the potential importance of developing specific inhibitors for GIVA-PLA2 that can penetrate the blood-brain barrier.

Figure 2
PLA2 may mediate excitotoxicity, cerebrovascular dysfunction and oxidative stress in AD. Aβ leads to increases in intracellular Ca2+ and activation of kinases in the ERK/MAPK pathway. GIVA-PLA2 activity and access to its phospholipid substrate ...
Figure 3
Potential role for GIVA-PLA2 in network dysfunction and behavioral abnormalities in AD. Aβ activates GIVA-PLA2, leading to the generation of AA and its metabolites. AA can increase neuronal excitation and synchronization, partly by elevating surface ...


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