Positive and negative effects of prostaglandins in Alzheimer's disease


  • Mohammad Javad Fattahi PhD,

    1. Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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  • Abbas Mirshafiey PhD

    Corresponding author
    1. Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
    • Correspondence: Abbas Mirshafiey, PhD, Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Box 6446, Tehran-14155, Iran. Email: mirshafiey@tums.ac.ir

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The aim of this review was to clarify the role of prostaglandins and prostaglandin receptors in the immunopathology of Alzheimer's disease. A PubMed search was done using the key word, ‘Alzheimer's disease’ in combination with the term ‘prostaglandins’. Articles from the past 10 years were preferentially selected but important ones from the past 20 years were also included according to the authors' judgment. Alzheimer's disease is characterized by pathological hallmarks such as extracellular deposition of the amyloid β-peptide, the appearance of intracellular neurofibrillary tangles, extensive neuronal loss and synaptic changes in the cerebral cortex and hippocampus. These processes induce inflammatory pathways by activating microglia, astrocytes and infiltrating leukocytes that produce inflammatory mediators including cytokines and prostaglandins.Prostaglandins are small lipid mediators derived from arachidonic acid by multi-enzymatic pathways in which cyclooxygenases and phospholipases are the rate-limiting enzymes. In the central nervous system, prostaglandins exhibit either neurotoxic or neuroprotective effects by acting on specific G-protein-coupled receptors that have different subfamilies and differences in their selective agonists, tissue distribution and signal transduction cascades. Further studies on the role of prostaglandins in Alzheimer's disease may contribute to clarification of their neuroprotective actions, which may lead to the development of successful therapeutic strategies.

ALZHEIMER'S DISEASE (AD) is a chronic neurodegenerative disorder and the most important cause of dementia in the elderly. AD is characterized by progressive memory loss, changes in personality, and cognitive decline.[1] The majority of AD cases are sporadic, and approximately 5–10% of cases have autosomal dominant inheritance with onset before 65 years of age (early-onset familial AD). Molecular analysis has made it possible to identify mutations in different genes that are responsible for familial forms of AD and enhancing the deposition of amyloid-β (Aβ) peptide. These genes include the amyloid precursor protein, presenilin 1, and presenilin 2.[2, 3] Moreover, vascular, environmental, and socioeconomic factors, as well as life habits and medication have been identified to be associated with increased or decreased AD risk.[4] The major neuropathological hallmarks of AD are extracellular deposits of Aβ that condense to form senile plaques surrounded by astrocytes and microglial cells (amyloid hypothesis), intracellular neurofibrillary tangles (NFT) composed of the hyperphosphorylated microtubule associated protein tau and synaptic and hippocampal neuronal loss.[5, 6] Dysregulation in the metabolism of β-amyloid precursor protein leading to deposition of Aβ begins several decades before the appearance of the first clinical symptoms of AD. There are factors that promote or delay emergence of the disease during this time. Some mediators associated with inflammatory and immune functions may be important in this context.[7, 8] Although neuroinflammation is considered to be a secondary phenomenon according to the amyloid hypothesis, it has been suggested to cause degenerative changes in neurons (inflammation hypothesis). This hypothesis is supported by epidemiological retrospective observations that extended the use of non-steroidal anti-inflammatory drug (NSAIDs) results in a reduced risk of AD.[9] The inflammatory processes in AD involve mainly effector mechanisms and cells of the innate immune response, such as components of the complement cascade, activated microglial cells and astrocytes that produce acute-phase proteins, cytokines and prostaglandins (PG).[7, 10]

In this review, we will discuss the major properties of PG and their expanding roles in biology and medicine and in the second section, we clarify the role of PG and PG receptors in the immunopathology of AD.


We performed a PubMed search using the key word ‘Alzheimer's disease’ in combination with the term ‘prostaglandins’. Articles from the past 10 years (2002–2012) were preferentially selected but important ones from the past 20 years were also included according to the authors' judgment. Only English-language articles were chosen. A final total of 124 articles was used for the review that appeared to highlight current understanding and scientific advancement in the pathogenesis and therapeutic approaches of AD.


Prostaglandins are small lipid inflammatory mediators that are generated by complex enzymatic reactions that begin with arachidonic acid (AA) release from membrane phospholipids by cytosolic phospholipase A (cPLA). AA is then metabolized by two pathways, lipooxygenase and cyclooxygenase (COX). In the latter, COX and PG synthase enzymes metabolize AA to PG including prostaglandin E2 (PGE2), prostaglandin F (PGF), prostaglandin D2 (PGD2), prostacyclin (PGI2) and thromboxane (TXA2), which play pivotal roles in the modulation of physiological systems and pathophysiological processes.[11, 12] PG exert their effects via the activation of specific G-protein-coupled receptors (GPCR).[12] PG receptors have various subfamilies including the D prostanoid receptor (DP), E prostanoid receptors 1–4 (EP 1–4), F prostanoid receptor (FP), prostacyclin receptor (IP) and thromboxane receptor (TP), which bind to PGD2, PGE2, PGF, PGI2 and TXA2, respectively. These receptors are different in their selective agonists, tissue distribution and signal transduction pathways.[13] The limiting steps in the biosynthesis of prostanoids are the expression and activity of COX and the activation of phospholipases.[14] Different types of phospholipases are present in cells that hydrolyse phospholipids and produce lipid mediators and second messengers that play pivotal roles in regulating cellular functions. Among these, phospholipase A2 (PLA2) plays an essential role in altering cell activities, such as lipid domain reorganization, membrane phase properties changes, and membrane fluidity.[15] The PLA2 family includes cytosolic PLA2 (cPLA2), secretory PLA2 (sPLA2) and calcium-independent PLA2 (iPLA2).[16] Although cPLA2 preferentially releases AA, the major activity of iPLA2 is the release of docosahexaenoic acid,[17] which is a precursor for the synthesis of neuroprotectin D and also plays a role in regulating PG production.[18]

Some hormones and cytokines regulate PLA2 activity, for example, pro-inflammatory cytokines increase the activity of PLA2 and contribute to the increased production of PG.[19]

The COXs are heme-containing enzymes that exist in two major isoforms in mammals: COX-1 and COX-2. Although COX-1 and COX-2 have approximately 60% homology at the amino acid level and catalyze the same reactions, they have different patterns of expression and are encoded by different genes.[20, 21] COX-1 is constitutively expressed in many cells and tissues and is responsible for maintaining basic physiological functions and the baseline production of PG and thus is known as a ‘housekeeping’ enzyme, whereas COX-2 expression is induced by inflammatory mediators such as cytokines, growth factors, bacterial endotoxin and mitogens.[22, 23]


Prostaglandin D synthase (PGDS) is responsible for the biosynthesis of PGD2 and J series from the product of COX activity, prostaglandin H2 (PGH2). PGDS has two distinct isoforms: the lipocalin (brain) type PGDS (L-PGDS), which is responsible for PGD2 biosynthesis in the central nervous system (CNS), and the glutathione-dependent hematopoietic PGDS (H-PGDS) or spleen-type PGD2 synthase.[24-26] PGD2 regulates a wide variety of physiologic and pathologic processes.[27] PGD2 exerts its effects by activating two receptors, DP1 and chemoattractant receptor-homologous molecule expressed on T-helper 2 (Th2) cells (CRTH2)/DP2. DP1 activation by PGD2 causes the elevation of intracellular cAMP level, which is typically associated with modulation of cellular effector activity, whereas the CRTH2/DP2 receptor stimulation leads to increase of intracellular Ca+2 that induces Th2 cell responses such as cytokine production, migration and enhancement of their adhesiveness to endothelial surfaces.[25] PGD2 is degraded non-enzymatically to form PG of the J series, such as PGJ2, δ12-PGJ2, and 15-deoxy-δ12,14-PGJ2 (15d-PGJ2). 15d-PGJ2 was identified as a ligand for peroxisome proliferator-activated receptor-γ (PPAR-γ), which acts as a mediator of many anti-inflammatory effects of PGD2.[28] 15d-PGJ2 inhibits the production by monocytes/macrophages of several inflammatory mediators.[29] It blocks nitric oxide production as well as proteoglycan degradation.[30] When PGD2 is produced in a high concentration for activating PPAR-γ, it will be able to inhibit T lymphocyte proliferation and, consequently, the inflammatory response. In contrast, if PGD2 and its metabolites are produced in nanomolar concentrations it may be expected to activate T lymphocytes.[31, 32]


PGE2 is one of the most abundant PG generated in the body. It is a potent lipid mediator that regulates a wide range of physiological activities in the immune system and the other biological systems.[26, 33] Prostaglandin E synthase (PGES) is responsible for converting COX-derived PGH2 to PGE2. There are three different types of PGES: microsomal PGES-1 -2 (mPGES-1, -2); and cytosolic PGES (cPGES, p23). Glutathione-dependent mPGES-1 is preferentially coupled to COX-2 and is induced in response to various stimuli.[34, 35] Glutathione-independent mPGES-2 is a unique PGES that is constitutively expressed and linked to both COXs during the production of the PGE2 involved in both tissue homeostasis and disease.[27] cPGES is constitutively expressed and is preferentially coupled to COX-1 rather than COX-2 and its expression is not affected by pro-inflammatory stimuli.[36] PGE2 has different physiological effects by acting on four rhodopsin-like 7-transmembrane-spanning GPCR: EP1, EP2, EP3, and EP4, which have differences in binding affinity, signal transduction, tissue localization, and regulation of expression.[37] EP3 and EP4 are the most abundant of EP receptors and their binding affinity to PGE2 is higher than EP1 and EP2 receptors.[37] EP receptors link to different intracellular signaling molecules to mediate the effects of receptor activation on cell function. EP2, EP4 receptors couple to a Gs-type G protein that activates adenylate cyclase, increasing intracellular cAMP. EP1 links to Gαq and activates phosphatidylinositol metabolism, leading to mobilization of intracellular free Ca.2+ The EP3 receptor can couple to Gi or G12 for elevation of intracellular Ca,2+ inhibition of cAMP generation, and activation of the small G protein Rho.[12, 37, 38] The majority of the PG receptors are localized at the cell membrane, and some are present at the nuclear envelope.[39] Knock-out mouse experiments showed that PGE2 can exhibit both pro-inflammatory and anti-inflammatory responses, depending on receptor subtype, cell population, context of activation and receptor gene expression in tissues.[26, 40]


PGI2 is a potent vasodilator that is generated primarily by vascular endothelial cells.[41] It exerts its functions through a specific GPCR, called the IP receptor.[12] Both COX enzymes (COX-1/2) metabolize AA to the PG precursor PGH2, which is subsequently converted into PGI2 via prostacyclin synthase (PGIS), a member of the cytochrome P450 superfamily.[42, 43] The IP receptor is coupled predominately to a Gs subunit and in some circumstances with Gi- and Gq-dependent pathways. The Gs subunit leads to an increase in cAMP level, which is responsible for the vasodilatory and anti-thrombotic effects of PGI2.[12] PGI2 may also signal through the PPAR-γ pathway.[44] PGI2 exerts a regulatory effect within the cardiovascular system, thus acting as a physiological antagonist of TXA2.[45, 46] It has been identified that IP receptor signaling by promoting Th2 cell production of the anti-inflammatory cytokine, interleukin (IL)-10, inhibits Th2-mediated allergic inflammatory responses.[12, 47] PGI2 is the most frequent PG in synovial fluid in rheumatoid arthritis (RA) patients.[48] In RA and osteoarthritis, PGI2 acts as a pro-inflammatory lipid mediator.[42]


PGF is biosynthesized from PGH2 and other PG (PGE2, PGD2) by three enzymes.[49] It exerts its biological functions by binding to a prostanoid receptor, namely FP, with two differentially spliced variants (FPA, FPB). The FP receptor links to Gq protein for increasing the inositol phosphate accumulation, protein kinase C activation, and intracellular Ca+2 release.[50] In addition, stimulation of FP receptor leads to activation of G-protein Rho via a Gq-independent process, resulting in cytoskeleton rearrangement.[51] The FP receptor is the least selective of the PG receptors in binding the principal endogenous PG, PGD2 and PGE2 at nanomolar concentrations.[12] PGF plays a pivotal role in many physiological and pathological processes including the reproductive system, renal function, contraction of arteries, myocardial dysfunction, regulation of intraocular pressure and pain.[52-54] PGF is also associated with acute and chronic inflammatory diseases[55] and oxygen-deprived brain injury.[56] Basu et al. found that the oxidative metabolism of AA through both enzymatic (COX) and non-enzymatic (free radical) pathways is involved in endotoxin-induced inflammation in pigs, as indicated by significantly increased formation of F2-isoprostane (e.g. 8-iso-PGF) and PGF metabolite in plasma.[57] They also showed that the measurement of F2-isoprostanes in body fluids provides a reliable analytical tool to investigate oxidative stress-related diseases and inflammatory conditions.[58]

AD and PG

In AD patients the accumulation of Aβ and tau within the CNS results in activation of microglia and astrocytes involving a pro-inflammatory pathway that results in the release of potentially neurotoxic substances, including cytokines, reactive oxygen and nitrogen species, and PG, leading to degenerative changes in neurons.[9, 59]

AD and PLA2s

The levels of PG generation are regulated by the expression and activity of PLA2 and COXs. PLA2 have been implicated in neuronal homeostasis and memory formation. To study the role of PLA2 in the CNS, the investigators focused on the group IV cPLA2, the group VI iPLA2, and the group II sPLA2. Both cPLA2 and iPLA2 are constitutively expressed in neurons, and inhibition of them has resulted in the reduction of neurite outgrowth and loss of neuronal viability.[60, 61]

The oligomeric Aβ peptide, through a signaling pathway involving N-methyl-d-aspartate (NMDA) receptors and NADPH oxidase, activates cPLA2 and increases AA in neurons.[62] Overstimulation of this toxic process was shown to result in the impairment of mitochondrial function and neuronal apoptosis.[63] Among the sPLA2, sPLA2-IIA is involved in inflammatory disease.[64] Moses et al. found an increase in sPLA2-IIA mRNA expression in the hippocampal region of human AD brains in comparison with age-matched, healthy controls.[65] In addition, Chalbot et al. showed an increase of sPLA2-IIA activity in the cerebrospinal fluid (CSF) of AD patients, and suggested the possibility of using sPLA2-IIA as a biomarker of neuroinflammation.[66]

AD and COXs

COX-1 and COX-2 are constitutively present in the brain mainly in the neocortex and hippocampus neurons. These enzymes play various roles in normal neuronal function. In AD patients, it has been proposed that changes in COX-1 and COX-2 expression depend on the stage of the disease and the type of cells expressing these enzymes.[67, 68] COX-1 is upregulated in the frontal and temporal cortex of dementia patients.[69] Hoozemans et al. showed that COX-1 positive microglia are increased in AD and are associated with Aβ plaque.[67] In the early stages of AD, COX-2 expression is increased in neurons, while the number of COX-2-positive neurons is significantly decreased in the advanced stages of AD, due to selective degeneration of COX-2-expressing cells.[70, 71] Variation in COX-2 expression in the different stages of AD coordinates with PGE2 level in the CSF.[72] Although early epidemiological data suggest that COX inhibitors including NSAIDs could be effective in AD patients,[73] several recent clinical trials have indicated that these drugs may not be beneficial therapy for AD.[74, 75] It appears that NSAIDs and selective COX inhibitors might be effective if used before the onset of AD symptoms.[74]

AD and PGD2

PGD2 is the most frequent PG in the brain and it regulates physiological processes including sleep,[76] temperature and nociception.[77] PGD receptors (DP1 and CRTH2/DP2), which have opposite effects on cAMP generation, are also largely expressed in hippocampus and cerebral cortex. Liang et al. showed that PGD2 or the DP1 agonist BW245C can prevent neuronal injury in models of acute excitotoxicity. This effect was disrupted by protein kinase A (PKA) inhibitors, H89 and KT5720, indicating that PGD2 neuroprotection was dependent on downstream signals of increased cAMP. In contrast, the DP2 receptor induces neurotoxicity in both dispersed and organotypic neurons (Table 1).[78, 79] Mohri et al. found that in AD patients and in Tg2576 mice the levels of H-PGDS and DP1 are overexpressed in microglia and astrocytes within senile plaque, and the levels of their mRNAs upregulated in parallel with Aβ deposition. These results indicated that PGD2 may act as a mediator of plaque-associated inflammation in the AD brain.[80] L-PGDS was localized in amyloid plaque in both AD patients and in Tg2576 mice. It can couple to Aβ monomers and prevent Aβ aggregation. Based on these results it was suggested that L-PGDS is an Aβ chaperone and that inhibition of this activity could be related to the onset and progression of AD.[81]

Table 1. DP1 and DP2: CNS expression and signaling pathways
D prostanoid receptorsExpression in CNS regionsSignalingFunction
  1. CNS, central nervous system; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; DP, D prostanoid receptor.
DP1Thalamus, hypothalamus, cortex, hippocampus↑cAMPNeuroprotective
DP2/CRTH2Cortex, hippocampus, thalamus↓cAMPNeurotoxic

AD and PG of the J series

15d-PGJ2 is a PPAR-γ agonist that effectively inhibits the production of pro-inflammatory cytokines such as IL-12, IL-23 and IL-1β by activated microglia. These cytokines may limit the efficacy and safety of Aβ immunotherapy for the treatment of AD. In addition, 15d-PGJ2 suppresses the induction of CD14, MyD88, and Toll-like receptor 2 (TLR2) molecules that play pivotal roles in neuroinflammatory disease.[82] In addition, 15d-PGJ2 and other PPAR-γ agonists, troglitazone and ciglitazone, attenuate the Aβ-induced impairment of hippocampal long-term potentiation (LTP) in vitro, a possible beneficial effect on AD progression.[83] Arnaud et al. showed that PGJ2, a product of inflammation, modulates tau cleavage at Asp421 through caspase-mediated proteolysis. This event generates Δtau, an aggregation-prone form that may serve as an axis for cytotoxic protein aggregation in neuronal cells. This process is PPAR-γ independent and is an early event in AD tangle pathology.[84]

AD and PGE2

Montine et al. found that the level of PGE2 increases in patients with probable AD and suggested that PGE2 signaling may play a role in the development of AD.[85] PGE2 exerts different physiological functions in the CNS including both toxic and protective effects in a variety of neuronal tissues. These functions are mediated by the four PGE2 receptor subtypes, EP1–4,[86] which are differentially expressed on almost all organs, including the CNS.[21] Although EP4 expression in neurons is restricted to hypothalamic nuclei, other EP receptors are expressed in multiple brain regions including the hippocampus, striatum and cortex(Table 2).[86]

Table 2. EP1–4: CNS expression and signaling pathways
E prostanoid receptorsExpression in CNS regionsSignalingFunction
  1. CNS, central nervous system; EP, E prostanoid receptor; IP, prostacyclin receptor.
EP1Hypothalamus, thalamus, cortex, hippocampus↑IP3, Ca2+Neurotoxic
EP2Cortex, striatum, hippocampus, thalamus↑cAMPNeuroprotective/neurotoxic
EP3Hypothalamus, thalamus, cortex, hippocampus↓cAMPNeuroprotective/neurotoxic
EP4Hypothalamus, thalamus↑cAMPNeuroprotective/neurotoxic

The pharmacological inhibition or genetic deletion of the EP1 receptor reduces brain injury in models of oxygen glucose deprivation (OGD), excitotoxicity and cerebral ischemia.[87, 88] Studies have shown that the neuroprotective effects of the blocking of EP1 signaling are induced by exerting effects on Ca2+ homeostasis, regulating cerebral blood flow (CBF), or both. It has been identified that PGE2 binding to microglial EP2 and EP4 receptors blocks lipopolysaccharide- and ATP-induced cytokine synthesis in cultured microglia and in neuron–glia co-cultures.[89] In vitro studies indicate that the activation of the EP2 receptor is neuroprotective in paradigms of NMDA toxicity and OGD. Neuronal EP2-mediated protection is dependent on cAMP/PKA signaling.[90, 91] The EP2 receptor induces a very different response in the context of neuroinflammatory conditions. The data now demonstrate a neurotoxic effect of EP2 receptor signaling in activated microglia in vitro[92] and in vivo in paradigms of inflammatory neurodegeneration including the models of familial AD and Parkinson's disease (PD).[93, 94] EP2 signaling in a murine transgenic model of AD (APPSwe-PS1ΔE9) not only promotes an inflammatory oxidative response with an associated increase in the level of Aβ peptide but may also inhibit phagocytosis and clearance of accumulating Aβ peptides.[86, 93] The inhibitors of adenylate cyclase and PKA suppress EP2 receptor-mediated stimulation of Aβ production and may be useful targets for the development of drugs to prevent and treat AD.[95] PGE2 also exerts its effects on electrophysiological properties of hippocampal neurons by EP2 receptor, given that EP2-/- mice demonstrate major cognitive deficits in social memory tests associated with a deficit in long-term depression in the hippocampus.[96] The EP3 receptor is expressed mainly in the hypothalamus, where it exerts its physiologic function of regulating the febrile response.[97] Studies in models of glutamate excitotoxicity using hippocampal neurons and organotypic slices indicate a protective effect for EP3 neuronal signaling,[98] but pharmacological study using a selective agonist of the EP3 receptor showed increased infarct volume in the middle cerebral artery occlusion model of ischemia.[99] Shi et al. examined the function of EP3 receptor signaling in vivo in a model of neuroinflammation induced by exogenous Aβ42 peptides. They found that the EP3 receptor acts as a pro-inflammatory, pro-amyloidogenic, and synaptotoxic signaling pathway and may be associated with disease progression in AD.[100] PGE2/EP3 signaling can also reduce brain-derived neurotrophic factor (BDNF), a molecule necessary for normal hippocampal-dependent memory.[101] These opposite effects may, in part, be due to the existence of different isoforms of EP3 receptor that have different signaling pathways, desensitization and constitutive activity.[86, 102, 103]

Both EP4 and EP2 receptors are positively coupled to cAMP production, suggesting that the EP4 receptor may also function to confer neuroprotection in models of excitotoxicity or hypoxia. In the CNS, an in vivo study on pharmacologic stimulation with selective EP4 agonist showed neuroprotection.[86, 104] The EP4 receptor may play an important role in modulating the CBF dynamics in a model of transient focal cerebral ischemia.[105] In addition, the EP4 receptor exerts anti-inflammatory effects in vitro and in vivo via inhibition of pro-inflammatory cytokines in various models of inflammation, for example, in brain diseases characterized by inflammatory response.[106, 107] Hoshino et al. found that activation of the EP4 receptor causes its co-internalization with γ-secretase into endosomes and that this process is important for EP4-mediated stimulation of Aβ production by PGE2. As well, they showed that deletion of EP4 receptor decreases the brain level of Aβ in transgenic mice (APP23). These results suggest that the EP4 receptor could represent a useful molecular target for the treatment of AD.[95, 108]

AD and PGI2

Recent studies have found that vascular factors, for example, reduction in CBF, are involved in the mechanisms of AD.[109] AD patients have more severe atherosclerosis in large cerebral arteries in the brain than age-matched healthy controls.[110, 111] These lesions cause severe vascular narrowing that reduces CBF.[112] PGI2 is one of the most important vasodilators for increasing CBF and is a potent neuroprotective agent that exerts its functions by activating its IP receptor.[21, 113] In the CNS, IP receptor is expressed in the hippocampus, cerebral cortex and thalamus.[114] Cerebral ischemia also cooperates with AD pathology to enhance the clinical manifestations of the disease.[110] In ischemia models, it has been shown that PGI2 analogs reduce the neuronal loss in the hippocampal CA1 region and ameliorate memory impairment.[115, 116] Santhanam et al. showed that BDNF stimulates production of PGI2 and thus repairs the cerebral arterial wall.[117] It has also been shown that some pro-survival effects of PGI2 on the cerebral circulation might be mediated by PPAR-δ (PPAR-β/δ).[21] PPAR-β/δ is found in all cell types in the brain. It participates in the regulation of lipid metabolism in the brain. Kalinin et al. showed that some PPAR-β/δ agonists can reduce amyloid burden likely to be mediated by effects on amyloid clearance.[118-120]

AD and PGF

PGF is a potent vasoconstrictive agent that also may play a role in the progression of AD in which vascular injury is an axial phenomenon.[26, 121] Saleem et al. studied the role of PGF and its FP receptor in a model of focal cerebral ischemia in mice. They found that the FP receptor significantly enhances cerebral ischemic and excitotoxic brain injury.[122] The PG 13,14-dihydro-15-keto-PGF, a major metabolite of PGF, and the isoprostane 8-iso-PGF2a are directly associated with inflammation and the production of free radicals.[123, 124] Casadesus et al. found that both PGF and F2-isoprostanes (mainly 8-iso-PGF) increase in hippocampal tissue from AD patients, showing that brain inflammation and oxidative stress are significantly higher in AD compared to age-matched controls.[125]


Aβ and damaged neurons are potent inflammatory stimuli in the AD brain. These stimuli induce distinct, localized inflammatory reactions that initiate direct and indirect damage within the brain. PG play a central role in physiologic and inflammatory status in the CNS. Pharmacological inhibition or receptor gene inactivation have shown different and contrasting biological effects for various PG. They can induce both neuroprotective and neurotoxic effects depending on receptor subtype, cell population and receptor gene expression in the brain. Additional complexity is emerging, due to different effects of specific PG signaling cascades, which could be dependent on the context of neuronal injury, for example, in excitotoxicity/hypoxia paradigms versus inflammatory-mediated secondary neurotoxicity. Better understanding of differential PG receptor activation in the CNS is needed not only to provide insight into the pathogenesis of AD, but also to direct the development of selective and efficacious therapies that target toxic mechanisms while maintaining neuroprotective actions.


The authors do not have any conflicts of interest to report.