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(The FASEB Journal. 2005;19:1592-1601.)
© 2005 FASEB

Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs

Kirk P. Townsend and Domenico Praticò1

Center for Experimental Therapeutics and Department of Pharmacology; University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA

1 Correspondence: 3620 Hamilton Walk, John Morgan Building, Room 124, Philadelphia, PA, 19104, USA. E-mail: domenico{at}spirit.gcrc.upenn.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 ANTI-INFLAMMATORY PROPERTIES OF...
 ANTI-AMYLOID MECHANISMS OF...
 EXPERIMENTAL EVIDENCE SUPPORTING...
 OLD AND NEW MECHANISMS...
 CONCLUSIONS
 REFERENCES
 
Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder with dementia in the elderly. The AD brain pathology is characterized by deposits of amyloid-ß (Aß) peptides and neurofibrillary tangles but also (among other aspects) by signs of a chronic inflammatory process. Epidemiological studies have shown that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays its onset. Classical targets of NSAIDs include cycloxygenase, nuclear factor {kappa}B, and peroxisome proliferator-activated receptors. Modulation of these pathways, all of which have been implicated in AD pathogenesis, could explain the NSAID effect on AD progression. However, recent studies indicate that a subset of NSAIDs such as ibuprofen, indomethacin, and flurbiprofen may have direct Aß-lowering properties in cell cultures as well as transgenic models of AD-like amyloidosis. A renewed interest in the old and a discovery of new pharmacological properties of these drugs are providing vital insight for future clinical trials. In this review we will summarize how the combination of traditional (anti-inflammatory) and new (anti-amyloidogenic) properties of some NSAIDs is providing unprecedented opportunities for drug discovery and could potentially result in novel therapeutic approaches for the treatment of AD.—Townsend, K. P., Praticò, D. Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs.


Key Words: amyloid beta • APP metabolism • inflammation • central nervous system • NSAIDs • cyclooxygenase • coxibs


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
ANTI-INFLAMMATORY PROPERTIES OF...
 ANTI-AMYLOID MECHANISMS OF...
 EXPERIMENTAL EVIDENCE SUPPORTING...
 OLD AND NEW MECHANISMS...
 CONCLUSIONS
 REFERENCES
 
ALZHEIMER’S DISEASE(AD) is the most common neurodegenerative disorder of the elderly and is characterized clinically by a progressive memory loss, as well as other cognitive impairments. AD is also the most frequent cause of dementia in the elderly, and the number of affected individuals doubles every 5 years after the age of 60, rising from a prevalence of ~1% at age 60 to >40% for individuals over 85 years old (1) .

The neuropathological hallmarks of AD include abundant deposits of amyloid ß (Aß) fibrils in senile plaques (SPs), accumulation of abnormal tau protein filaments in neurofibrillary tangles (NFTs), and extensive neuronal degeneration and loss (2) . AD brains also exhibit a number of pathological abnormalities, including a profound loss of synapses, profuse reactive gliosis, microglial activation, and inflammatory processes (3) . Although classical defined inflammation includes edema and neutrophil invasion, such features are not seen in the AD brain, yet increasing evidence indicates that a large number of factors known to be major participants in inflammatory processes are a constant feature of AD neuropathology. The list of inflammation mediators that have been detected in the AD brain is long and includes activated complement proteins, cytokines, chemokines, proteases and their inhibitors, proteoglycans, growth factors, and miscellaneous enzymes (4) . This observation suggests a central role for chronic inflammation in AD pathogenesis, supporting the "inflammatory hypothesis" of the disease (3) . This hypothesis postulates two possible scenarios: 1) neurodegeneration in AD brain is secondary to an inflammatory response to SPs and NFTs rather than to these hallmarks themselves; 2) inflammation triggers the formation of SPs and NFTs, which in turn activates immune reactions that drive a self-sustaining "autodestructive" process.

Support for this hypothesis comes from genetic studies showing that polymorphisms of some inflammatory genes (i.e., interleukin (IL) -1{alpha}; IL-1ß; tumor necrosis factor (TNF) {alpha}; {alpha}2-macroglobulin, {alpha}1-antichimotrypsin) enhance the risk of AD (5) . Epidemiological studies show that nonsteroidal anti-inflammatory drugs (NSAIDs) (Fig. 1 ) may delay or prevent the onset of AD, slow its progression and decrease the severity of cognitive symptoms (6 7 8) . All this information represents the rationale for a series of clinical trials of different NSAIDs in AD patients. However, after some initial positive results with indomethacin, and diclofenac in small pilot studies, much longer and larger trials using different NSAIDs (i.e., naproxen, rofecoxib) later failed to show any beneficial effect (9 , 10) . Below, we will summarize first the classical targets for the anti-inflammatory actions of NSAIDs, which indirectly could influence amyloidosis. In a separate section, we will focus our attention on the more recent data supporting a more direct anti-amyloidotic activity for these drugs.



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  		Figure 1. Chemical structures of some classical NSAIDs, all of which are nonselective COX inhibitors.


   ANTI-INFLAMMATORY PROPERTIES OF NSAIDs
TOP
 ABSTRACT
 INTRODUCTION
 ANTI-INFLAMMATORY PROPERTIES OF...
ANTI-AMYLOID MECHANISMS OF...
 EXPERIMENTAL EVIDENCE SUPPORTING...
 OLD AND NEW MECHANISMS...
 CONCLUSIONS
 REFERENCES
 
Cyclooxygenase
In 1893, German chemist Felix Hoffman synthesized a new molecule with analgesic property called acetylsalicylic acid or aspirin. From this moment a new class of drugs, collectively called NSAIDs, was introduced; since then, this family has grown enormously. Today they still represent the most widely used therapeutic agent in the world. However, the principal mechanism of action of these drugs was elucidated only in 1971, when it was shown that the ability of these drugs to suppress inflammation resides primarily in their ability to inhibit the cyclooxygenase (COX) enzyme, which would result in reduced formation of inflammatory prostaglandins (11) . Traditional NSAIDs reversibly inhibit the COX activity of the enzyme prostaglandin H synthase, which converts arachidonic acid to prostaglandin H2, the immediate precursor of various prostaglandins and thromboxane (12) . Today there are at least three known isoforms of this enzyme, which have high structural identity but are different in substrate and inhibitory selectivity, as well as intracellular localization (Fig. 2 ). COX-1 is expressed in many tissues and its metabolic products are considered to be involved in cellular housekeeping functions (13) . COX-2 has lower expression levels in tissues under normal circumstances, but is increased during inflammatory responses (13) . It has recently been reported that there is another COX enzyme formed as a splice variant of COX-1, denoted as COX-3 (14) . However, its functions are still unknown and it is possible that this isoform is not expressed in humans; thus, its relevance to the effects of NSAID in humans is questionable (15) .



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  		Figure 2. Representative metabolic pathways of prostaglandin formation. PLA2: phospholipase A2; PG: prostaglandin; Tx: thromboxane.

Particular attention has recently focused on the role these enzyme isoforms (COX-1 and COX-2) could play in AD pathogenesis. This has been suggested by reports showing elevated COX-1 and COX-2 protein levels in the AD brain compared with age-matched controls (16 17 18) . Immunohistochemistry studies of COX-1 and COX-2 expression in the brain have shown them to be restricted to microglia and neurons, respectively (18 , 19) . A semiquantitative immunocytochemical investigation showed that neuronal COX-2 expression in the hippocampus directly correlates with the severity of dementia (20 , 21) . This increased neuronal COX-2 expression in AD has been reported to be concomitant with that of NFT formation (18) . However, conflicting data regarding the expression of both COX isoforms in AD brain have been reported. For instance, COX-1 was reportedly not altered in neuronal cells, but was found to be increased in microglia from AD patients compared with controls (22) . A more complex picture exists for COX-2, where both an increase and a decrease have been reported for its expression in AD brain compared with age-matched controls (23 , 24) .

In summary, from these data it is unclear how the enzyme level and/or activity relate to the amyloid deposition, and in particular whether they are primary or secondary events or just two independent processes. Data from animal models show that compared with wild-type littermates, the double transgenic Tg2576/PS1 mice have only a marginal increase in COX-2 immunoreactivity present in glial cells around amyloid plaques (25) . Some indirect evidence would suggest that COX-2 activity is increased as a function of age in brain slice culture from Tg2576 (26) . Recently we showed that in the Tg2576, while levels of COX-1 mRNA do not change with age or during the evolution of their phenotype, COX-2 mRNA increases only after amyloid plaques are deposited (15 months of age) (27) . Overexpression of human COX-2 in the Tg2576/PS1transgenic mice does not influence their amyloidotic phenotype at 12 months of age and has a small effect only when the animals are 20 to 24 months old (28) . No data are available on the behavior of these animals. Taken together, these data would suggest that COX-2 is involved only at the later stage of the AD-like phenotype and probably plays only a minor role in this animal model.

There is also some evidence showing that both COX-1 and COX-2 may contribute to inflammation in the central nervous system (CNS) (29 30 31) . Animal studies have shown that indeed NSAIDs such as indomethacin and flurbiprofen, both nonselective COX inhibitors, reduce microglia and astrocytes activation by suppressing the levels of inflammatory mediators, i.e., prostaglandin E2 (PGE2) and IL-1ß (32 , 33) . Thus, inhibition of both COX-1 and COX-2 seems to be desirable to reach an optimal anti-inflammatory effect in the CNS. However, more investigation is needed to better understand whether and how these two isoforms could contribute to neurodegeneration and inflammation and, finally, how their inhibition would influence AD onset, evolution, and progression.

Nuclear factor-{kappa}beta
Nuclear factor-{kappa}B (NF-{kappa}B) is a transcription factor involved in the regulation of several cellular target genes (34) . In the absence of stimulatory signals, NF-{kappa}B resides in the cytoplasm as a heterodimer by its physical interaction with an inhibitory phosphoprotein, I{kappa}B. Signals that induce activation of NF-{kappa}B cause its dissociation from I{kappa}B and subsequent entrance into the nucleus, where it induces expression of many genes involved in immune and inflammatory responses (35) . This factor is widely expressed in the CNS and is present in both neurons and glial cells, where it could be a positive regulator of genes whose products mediate acute-phase response, including nitric oxide and a full array of inflammatory cytokines (36) . In vitro data have consistently shown that different pathogenetic stimuli can activate this factor, including Aß peptides, and that different NSAIDs can directly prevent this activation with subsequent reduction of the inflammatory responses. Previous findings showed that NF-{kappa}B expression is increased in AD brains compared with controls and that, at least in vitro, this factor can regulate Aß formation in a neuronal cell line (37 38 39) .

Confirming the observation in human AD, activated NF-{kappa}B is increased in brains of Tg2576 compared with wild-type littermates, and this increase is associated with the deposition of amyloid (27) . In the same study, Tg2576 receiving indomethacin showed a reduced activation of this factor in the same brain regions where an anti-amyloidotic effect associated with a decreased reactive astrocytosis was observed. Finally, in vitro evidence indicated that NF-{kappa}B activity is required to mediate the indomethacin-induced reduction of the amyloid synthesis (27) . These results support the hypothesis that the beneficial effect of indomethacin in AD could be mediated not only by a COX-dependent mechanism, but also by a COX-independent one, which involves the suppression of the activation of NF-{kappa}B.

Peroxisome proliferator-activated receptor-{gamma}
Another mechanism that has been implicated in the anti-inflammatory action of NSAIDs is activation of the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}). This receptor is a member of the nuclear receptor family of transcription factors, which includes different proteins mediating ligand-dependent transcriptional activation and repression (40) . Several natural and synthetic (pharmacological) ligands for PPAR-{gamma} have been described. Among the natural ligands, some prostaglandins and leukotrienes have been shown, at least in vitro, to be potent activators of the PPAR{gamma} (41) . Its cellular activation is associated with a reduction in the expression of several inflammatory genes (42) and the production of inflammatory cytokines (i.e., IL-1, IL-6, TNF{alpha}) (43) . At high concentration some NSAIDs act as direct PPAR{gamma} ligands and, as a consequence, reduce cytokine production (44) . In vitro studies have shown that indomethacin and ibuprofen can both activate PPAR{gamma} in microglia, reducing the Aß-mediated secretion of inflammatory cytokines and neurotoxicity (45) . Similar observations were obtained with the same NSAIDs when a neuroblastoma cell line was also challenged with Aß (46) . Considering that some reports indicated that this nuclear receptor is involved in AD pathology, it is possible that some of the beneficial effects from NSAIDs usage seen in AD could be ascribed to their action on PPAR{gamma} and subsequent reduction of brain inflammation (16 , 46) . Immunoblot analysis of cerebral PPAR-{gamma} protein levels has been reported to be increased in the cytosolic homogenates from temporal lobe of AD compared with age-matched controls, suggesting that activators of this receptor may alter AD clinical course via this pathway (16) . However, polymorphisms in PPAR-{gamma}, which have been associated with lipid metabolism disorders, have not shown an associated increased risk for AD (47 , 48) . Two studies have examined the effects of orally administered pioglitazone (a direct agonist of this receptor) on AD-like pathology in the AD mouse mode. Heneka et al. reported that 7 days of treatment with this drug significantly decreased the area of Aß 1-42-positive amyloid deposits in the hippocampus and frontal cortex (49) . In the earlier study of Yan and colleagues, a lower daily dose of pioglitazone had failed to significantly reduce amyloid levels even when administered for a longer period (50) . However, since only ~18% of orally administered pioglitazone crosses the intact blood-brain barrier in mammals (51) , it seems likely that drug dosage may be critical to observe an effect in the CNS.

In summary, it is evident that more work is required to fully elucidate the role of PPAR{gamma} in AD pathogenesis and in inflammation of the CNS in general.


   ANTI-AMYLOID MECHANISMS OF NSAIDs
TOP
 ABSTRACT
 INTRODUCTION
 ANTI-INFLAMMATORY PROPERTIES OF...
 ANTI-AMYLOID MECHANISMS OF...
EXPERIMENTAL EVIDENCE SUPPORTING...
 OLD AND NEW MECHANISMS...
 CONCLUSIONS
 REFERENCES
 
Aß physical properties
One of the neuropathological hallmarks of AD is the presence of amyloid plaques. The primary components of these plaques are 40- and 42-residue peptides, denoted as Aß1-40 and Aß1-42, which are derived from the proteolytic cleavage of the parent molecule, the ß-amyloid precursor protein (ßAPP) (52) . Alzheimer’s brain-derived or synthetic Aß peptides are amphipatic and tend to auto-polymerize at a rate that is dependent on the physiochemical properties [pH, ionic strength] and conditions [temperature, agitation] of their aqueous environment. Studies of the in vitro aggregation of these peptides have provided support for the idea that their aggregation is linked not only to amyloid plaque formation but also to AD pathogenesis. In fact, Aß1-42, which has been shown to have a higher propensity to aggregate than the Aß1-40 variant (53) , is up-regulated by most of the genetic mutations that have been linked to familial forms of AD (54) . Thus, with regard to Aß fibrillogenesis, Aß1-42 has been implicated in forming the seed to which monomeric forms of Aß associates noncovalently to form nuclei, which then grow into soluble protofibrils and eventually into insoluble fibrils. Early reports suggested that these Aß fibrils initiate a cascade of events that results in neuronal cell death (55) . Current evidence suggests it is the active process of Aß fibrillization, rather than the soluble aggregates of Aß (also called oligomers/protofibrils) or even the insoluble amyloid fibrils, that may be responsible for synaptic dysfunction in AD (56) .

Agents that prevent, halt, and/or reverse the process of Aß fibrillization safely in vivo may be of therapeutic value in the treatment of AD. Today there is evidence suggesting that some NSAIDs can also directly or indirectly interfere with these processes, modulating the ability of these peptides to form aggregates at least in vitro (57) .

In vitro incubation of PGH2, the common prostaglandin endoperoxide precursor (Fig. 2 ), with Aß1-42 peptide enhanced its oligomerization in a time-dependent manner, suggesting that prevention of its synthesis by NSAIDs could also result in less fibril formation (58) . In an analogous in vitro Aß fibrillogenesis system, it was further shown that the addition of aspirin (1 mM) was able to oppose the spontaneous fibril formation by Aß1-42 as well as the enhancement seen by the addition of various lipids (59) .

ßAPP metabolism
ß-APP metabolism generally is divided into amyloidogenic (yielding Aß) and non-amyloidogenic (no Aß) pathways, which are controlled by enzymes collectively termed secretases. In the amyloidogenic pathway the ß-APP cleavage enzyme (BACE) mediates the amino termini cleavage of Aß from ß-APP resulting in the release of sAPPß and a cell membrane-associated fragment, denoted C-terminal fragment-ß (CTF-ß). If CTF-ß is then processed by the {gamma}-secretase complex (which includes presenilin-1 or -2, coupled with nicastrin, APH-1, and PEN-2), this event results in the subsequent release of Aß and a putative signal peptide CTF-{gamma} intracellularly (60) . In the non-amyloidogenic pathway, ß-APP is cleaved within the Aß peptide portion, thus precluding the generation of either Aß1-40 or Aß1-42 (Fig. 3 ). However, unlike the definitive identities of the amyloidogenic secretases, the putative {alpha}-secretase(s) mediating the non-amyloidogenic processing of APP remains speculative (some possible members include ADAM10 and TACE) (61) .



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  		Figure 3. Schematic representation of the non-amyloidogenic ({alpha}-secretase pathway) and amyloidogenic (ß-/{gamma}-secretase pathway) processing of the ß amyloid precursor protein (ßAPP) into cell free metabolites (APP-s{alpha}, APP-sß, Aß) and cell-associated metabolites (CTF-{alpha},ß,{gamma}).

Indomethacin and aspirin can both suppress the secretion of sßAPP, but not Aß, from human platelets when activated by common aggregating agents such as collagen and arachidonic acid (62) . Other reports have shown that some NSAIDs can also modulate the secretion of sßAPP from different neuronal cell lines, astrocytes, and neurons via a protein kinase C (PKC) -mediated mechanism (63 , 64) . In vitro studies addressing the effects of different nonselective COX isoform inhibitors (sulindac sulfide, R/S-fluriprofen, fenoprofen, ibuprofen, indomethacin) on Aß1-40 and Aß1-42 production have shown that they inhibit the production of Aß1-42 whereas Aß1-40 levels largely remain unchanged in glial and non-neuronal cells (65) . This Aß1-42 selective effect suggests that these NSAIDs might be mediating their effects in a {gamma}-secretase-dependent manner (66) . COX-2 selective inhibitors (e.g., celecoxib) (Fig. 4 ) were shown to actually increase the production of Aß1-42, suggesting that this inhibition might not recapitulate the putative {gamma}-secretase inhibitor effects of nonselective NSAIDs. One study recently showed that neither COX-1 nor COX-2 deficiency could alter sulindac sulfide selective inhibitory effects on Aß1-42 (65) reinforcing the concept that a COX-independent pathway might be mediating the selective Aß1-42 lowering effects of some NSAIDs. Attempts to implicate other classical NSAID targets (i.e., 12/15 lipoxygenase, PPAR-{gamma}, or NF-{kappa}B) have not provided support for them in their selective Aß1-42-lowering effect (67 , 68) . Nonetheless, Gasparini et al., using a neuroblastoma cell line, showed a lack of Aß1-42 selective inhibitory action for the same drugs (69) . These conflicting results could be explained by the different cellular systems used, which may have differently skewed ßAPP metabolic pathways as well as NSAIDs sensitivity.



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  		Figure 4. Chemical structures of selective COX-2 inhibitors: celecoxib, rofecoxib, valdecoxib, parecoxib.

In conclusion, from these studies it appears that the ability to modulate Aß levels is confined mainly to NSAIDs, which are nonselective COX inhibitors, whereas selective inhibitors for COX-1 (sc-560) and COX-2 (sc-125, and celecoxib) have no effect.

NSAIDs in animal models of AD-like amyloidosis
In recent years, several studies have been performed using different NSAIDs in animal models of AD-like amyloidosis, which recapitulate only some of the aspects of the human disease (70) . Depending on the duration of treatments, all these studies can be divided in two major categories: short- and long-term studies (Table 1 and Table 2 ). Unfortunately, the outcome measures have varied from that of CNS amyloid plaque burden determination by immunohistochemistry to that of high-salt, RIPA, and/or formic acid extractable Aß1-40 and Aß1-42 brain levels determined by ELISA. This has made inter-report comparisons of the efficacy and, more important, the putative mechanism(s) by which the respective NSAIDs might mediate their anti-amyloidogenic effect more difficult to ascertain. In this article, due to space limitation, we will not mention the outcomes of each study published, but we will summarize only some of them as a representative example of the two groups. However, the two tables will display all the studies that have been published so far.


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  		Table 1. Long-term studies with NSAIDs in animal models of AD-like amyloidosis


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  		Table 2. Short-term studies (3 days treatment) with NSAIDs in Tg2576 mice

Lim et al. first reported that chronic administration of ibuprofen to Tg2576 reduces total Aß levels, Aß burden, and brain inflammation (71) . By contrast, in another study Tg2576/PS1 mice, despite receiving the same amount of ibuprofen, did not show any reduction in total Aß immunoreactivity (Aß burden) (72) . Indomethacin given to Tg2576 starting at 8 months of age until they were 15 months old significantly reduced soluble Aß1-40 and Aß1-42 in cortex and hippocampus, and insoluble Aß1-40 and Aß1-42 in the hippocampus. Consistently, these mice showed a significant reduction in their cerebral amyloid burden (27) . Celecoxib, a selective COX-2 inhibitor, has been tested in Tg2576/PS1 mice but no significant difference with placebo was reported in terms of Aß load in the cortex and hippocampus (72) . We have confirmed this observation in Tg2576 chronically treated with nimesulide, another preferential COX-2 inhibitor (27) .

In a short-term study using a 3-day dosing paradigm, 3-month-old female Tg2576 mice were gavaged daily with the different NSAIDs (nabumetone, naproxen, aspirin, ketoprofen, diclofenac, piroxicam, diflunisal, fenoprofen, sulindac, indomethacin, ibuprofen, flurbiprofen, or meclofen), and the measured outcome was brain formic acid-extractable Aß1-40 and Aß1-42 levels as determined by ELISA. The authors found that at a 50 mg/kg dose only meclofen could modestly (<20%, p<0.03) lower Aß1-40 levels. Significant reductions in Aß1-42 levels were seen with flurbiprofen (70%), indomethacin (35%), fenoprofen (24%), meclofenamic acid (80%), sulindac (26%), diclofenac (17%), and diflunisal (20%). Further, characterization of the potent Aß1-42 lowering effect of flurbiprofen was dose-dependent but not enantiomer specific (both R-flurbiprofen and S-flurbioprofen displayed similar potencies) (66) . The similar effects of the flurbioprofen enantiomers are important in that the R-flurobioprofen does not affect COX activity, suggesting that flurbiprofen in vivo Aß1-42 lowering effect does not depend on its ability to inhibit COX enzymes. However, in a more recent report those results were not duplicated (73) .


   EXPERIMENTAL EVIDENCE SUPPORTING NOVEL MECHANISMS OF ACTION FOR NSAIDs
TOP
 ABSTRACT
 INTRODUCTION
 ANTI-INFLAMMATORY PROPERTIES OF...
 ANTI-AMYLOID MECHANISMS OF...
 EXPERIMENTAL EVIDENCE SUPPORTING...
OLD AND NEW MECHANISMS...
 CONCLUSIONS
 REFERENCES
 
As mentioned earlier, there is emerging evidence that a subset of NSAIDs has a direct anti-amyloidotic effect. Below we will summarize the experimental data in support of this novel and exciting finding.

In their original report, Weggen et al. showed that some NSAIDs lower Aß levels in fibroblasts genetically deficient for COX-1 and COX-2 (65) . Another report showed that COX-1 (sc-560) and COX-2 (sc-125) selective inhibitors do not reduce either Aß1-40 or Aß1-42 (66) . In the quest for novel mechanisms of action of this class of drugs, another group more recently provided evidence that some NSAIDs play their Aß-lowering effect by inhibiting the small GTP binding protein Rho and its effector, Rho-associated kinase (Rock) (74) . Another COX-independent mechanism that has been invoked regards a possible interaction between some NSAIDs and a member of the ATP binding cassette transporter family, called the multidrug resistance protein-4 (MRP4). This protein is widely expressed in different tissues and organs; its role is to transport several substrates including cyclic nucleotides, steroids, and prostaglandins (75) .

However, the novel mechanism that has received the most attention is the fact that some NSAIDs could, at least in vitro, shift the ßAPP metabolism toward shorter and less fibrillogenic forms of the Aß peptides. Thus, ibuprofen, sulindac, and indomethacin can modulate this metabolism to specifically generate less Aß1-42 and more soluble Aß1-38 by interfering directly with the activities of two important enzymes in this metabolic pathway, i.e., ß- and {gamma}-secretases. Several recent studies using cell-free system assays enriched for {gamma}-secretase activity provided evidence that the selective effect described above is most likely secondary to a direct inhibition of the {gamma}-secretase activity (68 , 76 , 77) . Notably, this subset of NSAIDs would not share the potential toxicity of the classical {gamma}-secretase inhibitors since they do not influence the Notch pathway (78) . Taken together, these data are very exciting because for the first time we have the possibility to modulate this pathway without any side effect. However, a recent study failed to confirm the selective reduction of brain Aß1-42 after treatment of Tg2576 or guinea pig primary neuronal cells with the same NSAIDs that have been shown to modulate in vitro {gamma}-secretase (73) .


   OLD AND NEW MECHANISMS OF ACTION FOR NSAIDs: CLINICAL IMPLICATIONS
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 ABSTRACT
 INTRODUCTION
 ANTI-INFLAMMATORY PROPERTIES OF...
 ANTI-AMYLOID MECHANISMS OF...
 EXPERIMENTAL EVIDENCE SUPPORTING...
 OLD AND NEW MECHANISMS...
CONCLUSIONS
 REFERENCES
 
From the review of the growing literature on NSAIDs and AD, it is evident that both in vitro and transgenic animal studies are clearly providing the rational support for the data derived from epidemiological studies (Tables 1 , 2 ; Table 3 ). Nonetheless, recent long-term, prospective, randomized placebo-controlled clinical trials with NSAIDs have produced negative results (Table 3) . Although results obtained in small pilot trials with indomethacin and diclofenac have been encouraging, their interpretation is confounded by high dropout rates due to gastro-intestinal side effects (6 , 79) . Since selective COX-2 inhibitors have a reduced rate of these complications, they have been used in AD with great expectations. Unfortunately, these drugs failed to slow the progress of AD, suggesting that the disease was too advanced or that COX-2 is not involved in its pathogenesis. The latter hypothesis is supported by a recent negative study with rofecoxib in subjects with mild cognitive impairment, the earliest stage of AD (80) . This class of drugs has recently been shown to increase the risk of cardiovascular events. As a result, some of these drugs have been withdrawn from the market and some clinical trials halted, among them a trial with celecoxib in AD (81) .


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  		Table 3. Clinical trials with NSAIDs in AD

The discovery that some, but not all, NSAIDs can reduce Aß formation and deposition could help to clarify the apparent discrepancy between these conflicting results. Thus, it is not totally surprising that the results of clinical trials with naproxene, rofecoxib, and celecoxib were negative since these compounds have the least potency in modulating Aß in experimental models (65 , 66 , 69) . Nonetheless, some of these negative results have questioned the "inflammatory hypothesis" of AD, supporting the notion that it is not the COX-dependent effect of NSAIDs but the anti Aß mechanism(s) that is responsible for these effects. It is important to remember that most of the in vitro anti-amyloid effects are achieved by high drug concentrations and their anti-inflammatory effects by low µM levels. Moreover, different NSAIDs have diverse potency in crossing the blood-brain barrier because of their variable lipophilicity. As a result, the same dose of one compound will have actual levels in the brain much higher or lower that another one (82) . Finally, it is possible that their activity is influenced by a preferential accumulation in particular areas and compartments of the CNS, which will then reflect their therapeutic efficacy. These are all central issues that need to be addressed because they will provide the basis for the rational selection of the most appropriate NSAIDs, its dosage and the duration of the treatment in future clinical trials. These studies will definitively answer the question of the beneficial effect of this therapeutic approach in AD.


   CONCLUSIONS
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 ABSTRACT
 INTRODUCTION
 ANTI-INFLAMMATORY PROPERTIES OF...
 ANTI-AMYLOID MECHANISMS OF...
 EXPERIMENTAL EVIDENCE SUPPORTING...
 OLD AND NEW MECHANISMS...
 CONCLUSIONS
REFERENCES
 
AD is a complex and chronic disease for which the current therapeutic tools offer only a moderate symptomatic relief. Epidemiologic evidence, animal studies and in vitro data have strongly supported the idea that some NSAIDs have potential disease-modifying properties. Nonetheless, large, prospective, and randomized clinical trials have produced negative results, shedding some doubts on the inflammation hypothesis of AD. Several possible reasons for these findings have been suggested, among them the stage of the disease when the therapy is initiated, the different drugs and dosages used, and the levels that the drug of interest reaches in the CNS. The recent discovery that some but not all the NSAIDs besides their classical anti-inflammatory action manifest anti-amyloidotic properties supports the novel notion that a combination of both activities might be required to reach the fullest therapeutic results. Thus, it is not surprising after all that the results of recent trials are negative, since none of the compounds used (rofecoxib, naproxene) has this dual activity. Ongoing clinical investigations with ibuprofen and flurbiprofen will provide us with important information to test this hypothesis.

In conclusion, the recent renewed interest in this old class of drugs for AD treatment represents an important starting point that could lead us to the identification for the first time of disease-modifying agents for such a devastating disease.


   ACKNOWLEDGMENTS
 
The described work from the authors’ laboratory was funded by grants from the National Institute of Health (AG-11542, AG-22512) and the Alzheimer’s Association (IIRG-02-4010).


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 ANTI-INFLAMMATORY PROPERTIES OF...
 ANTI-AMYLOID MECHANISMS OF...
 EXPERIMENTAL EVIDENCE SUPPORTING...
 OLD AND NEW MECHANISMS...
 CONCLUSIONS
 REFERENCES
 

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