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provided by Spiral - Imperial College Digital Repository REVIEW ARTICLE published: 18 May 2010 AGING NEUROSCIENCE doi: 10.3389/fnagi.2010.00020 NSAIDs: how they work and their prospects as therapeutics in Alzheimer’s disease

Magdalena Sastre* and Steve M. Gentleman

Centre for Neuroscience, Division of Experimental Medicine, Imperial College London, London, UK

Edited by: There is signifi cant epidemiological evidence to suggest that there are benefi cial effects of Elena Galea, Universitat Autònoma de treatment with non-steroidal anti-infl ammatory drugs (NSAIDs) in Alzheimer’s disease, although Barcelona, Spain these effects have not been reproduced in clinical trials. The failure of the clinical trials may be Reviewed by: Sue T. Griffi n, University of Arkansas for attributed to several possible facts: (1) NSAIDS may have been delivered too late to patients, Medical Sciences, USA as they may only be effective in early stages of the disease and possibly counterproductive in Kerry O’Banion, University of the late stages; (2) the benefi cial effect may depend on the drug, because different NSAIDs Rochester, USA may have different molecular targets; (3) the NSAID concentration reaching the brain and the Elena Galea, Universitat Autònoma de Barcelona, Spain duration of the treatment could also be critical, so increasing drug penetration is important in *Correspondence: order to improve the effi cacy and avoid secondary gastro-intestinal effects of the NSAIDs. Magdalena Sastre, Centre for In this report we analyze these different factors, with special emphasis on the role of NSAIDs Neuroscience, Division of in microglia activation over time. Experimental Medicine, Imperial College London, Hammersmith Keywords: NSAIDs, Alzheimer’s disease, microglia, PPARγ, amyloid Hospital, Du Cane Road, London, W12 0NN, UK. e-mail: [email protected]

Many infl ammatory pathways have been implicated in Alzheimer’s TEMPORAL PROFILE OF MICROGLIAL ACTIVATION disease (AD), yet these pathways are not suffi ciently well delineated A potential target of NSAIDs is thought to be the microglia to defi ne those processes and targets that may be pathogenic as associated with the senile plaques. This is supported by a study by opposed to those that may be protective. A clearer understand- Mackenzie and Munoz (1998) showing in non-demented patients ing of these distinctions is critical to the design of therapeutic that those treated with NSAIDs had three times less activated strategies. The fi nding that treatment with non-steroidal anti- microglia as non-treated controls. These data have been confi rmed infl ammatory drugs (NSAIDs) is associated with a reduced risk by in vivo treatment with NSAIDs in mouse models of AD, which and age of onset of AD reinforces the hypothesis that modulat- have shown decreases in microglial activation and in infl amma- ing infl ammation could have therapeutic effi cacy. The benefi cial tory mediators such as iNOS, COX and cytokines (Lim et al., 2000; effects of NSAIDs have also been associated with reductions in Aβ Heneka et al., 2005). Experiments carried out in cultured microglia generation, since experiments in vitro and in AD animal models have revealed that incubation with NSAIDs decreased the secretion indicate that certain NSAIDs are able to decrease Aβ levels, plaque of pro-infl ammatory cytokines and may increase Aβ phagocytosis size and tau phosphorylation (Yoshiyama et al., 2007; El Khoury (Lleo et al., 2007). However, the reduction of activated microglia and Luster, 2008). and astroglia by NSAIDs was not signifi cant in AD patients, indicat- However, clinical trials have failed to reproduce the benefi cial ing an age or stage dependent difference in the glial response i.e. in effects of NSAIDs in AD patients. This has led to further analy- their activation rate (Alafuzoff et al., 2000). Recently, these fi ndings sis of the previously published epidemiological data, which has have been backed up by observations indicating that microglia may revealed that the use of NSAIDs prevents cognitive decline in change from alternative to classical phenotype over time (Colton older adults if started in midlife (prior to age 65) rather than et al., 2006; Hickman et al., 2008; Jimenez et al., 2008; Lucin and late in life (Hayden et al., 2007). In addition, it was recently Wyss-Coray, 2009), although probably there is a heterogeneous shown that while NSAIDs may indeed protect those with health- population. In addition, a paper of Meyer-Luehmann et al. (2008) ier brains, they can accelerate AD pathogenesis in patients with using two-photon microscopy showed that microglia in the aged advanced stages of the disease (Breitner et al., 2009). This is mouse brain is less motile and posses fewer processes. Therefore, supported by studies in transgenic mice, in which NSAIDs can the response of NSAIDs may differ in “young” vs “old” microglia prevent the appearance of cell cycle protein markers in neurons (Figure 1). in young mice, but not after cell cycle entry has been initiated It has been hypothesized that early microglial activation in AD (Varvel et al., 2009). Therefore, it seems that the protective effects delays disease progression by promoting clearance of Aβ before of NSAIDs depend very much on the stage of the disease at which formation of senile plaques. It is conceivable that glial activation the medication is started as well as the duration of the treatment. is protective through mechanisms such as phagocytosis and clear- Here we discuss four possible reasons why clinical trials with ance of Aβ deposits (through release of insulin degrading enzyme, NSAIDs have been unsuccessful. IDE), forming a protective barrier between Aβ and neurons and

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FIGURE 1 | Different targets for NSAIDs. The response to NSAIDs may differ hand, different subsets of NSAIDs have different affi nity for targets such as depending on whether they are used in early stages of disease, in which COX1, COX2, NFκB, PPARγ or γ-secretase, resulting in a range of effects microglia present an alternatively activated phenotype compared with late including reductions in infl ammatory mediators, such as cytokines and stages which is associated with a classical microglia phenotype. On the other alterations in Aβ generation. secretion of growth factors, early in the disease (Wyss-Coray et al., 2008) and may become detrimental through the release of cytokines 2003; Maragakis et al., 2006; Wyss-Coray, 2006). In later stages, with and chemokines including IL-1β, IL-6, TNFα, IL-8 and MIP-1α persistent production of pro-infl ammatory cytokines, microglia (Hickman et al., 2008). These infl ammatory mediators modulate lose their protective effect (Hickman et al., 2008; Jimenez et al., immune and infl ammatory function and may also alter neuronal

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function. In addition, microglia from old transgenic mice have a shown to decrease the levels of secreted Aβ42 in cells as well as in decrease in the expression of the Aβ-binding scavenger receptors A animal models of AD (Weggen et al., 2001; Eriksen et al., 2003). (SRA), CD36 and RAGE, and the Aβ degrading enzymes IDE, nepri- Importantly, the generation of Aβ40 was largely unaltered by these lysin and MMP9, compared with wild-type controls (Hickman compounds, indicating that certain NSAIDs modulate rather than et al., 2008) (Figure 1). On the other hand, in aged human brain inhibit γ-secretase activity (Czirr and Weggen, 2006). In fact, NSAIDs many microglia are dystrophic showing morphological features seem to bind APP, instead of the γ-secretase (Kukar et al., 2008). indicative of senescence, such as fragmented cytoplasmic proc- Some positive effects on cognitive performance of AD patients esses (Streit et al., 2004). Therefore, overactivated and dysregulated have been observed with indomethacin and the (R)-enantiomer of microglia could cause uncontrolled infl ammation that may drive fl urbiprofen in phase-2 trials, while other NSAIDs without Aβ42 the chronic progression of AD (Mrak and Griffi n, 2005; Gao and reducing activity did not show benefi cial effects. However, recent Hong, 2008). clinical trials in mild AD cases revealed that R-fl urbiprofen (taren- Microglia can be primed or desensitized by a stimulus (such as fl urbil) does not slow cognitive decline or the loss of activities of Aβ), which prepares the cells for an enhanced or decreased response daily living (Green et al., 2009). In addition, epidemiological studies to a second challenge (Gao and Hong, 2008). Microglia in aged or report that the protective effect of NSAIDs seems to be independent diseased brains are primed and usually behave differently to those of the Aβ42 reducing activity of the NSAID (Szekely et al., 2008a; in younger individuals (Gao and Hong, 2008). Thus, it is likely that Vlad et al., 2008). microglia do not respond equally to anti-infl ammatory therapy Besides targeting molecules such as COX and γ-secretase, some in old age and therefore, treatment of patients with NSAIDs in NSAIDs such as ibuprofen, naproxen and indomethacin can acti- advanced stages of the disease may not produce any benefi t. vate PPARγ (Jaradat et al., 2001). PPARγ inhibition regulates the One of the most controversial points is to establish whether transcription of pro-infl ammatory genes, such as IL1β; therefore microglia are “oversaturated” at a certain age or whether there is activation of PPARγ consequently inhibits the infl ammatory a loss of function. The debate on microglia function in AD pro- response. In addition, we found that PPARγ activators are able to gression has been intensifi ed by a recent report showing that AD decrease total Aβ levels under infl ammatory conditions by affecting animal models with nearly complete ablation of microglia did not BACE1 transcription (Sastre et al., 2006b, 2008). Recently it was display differences in plaque formation (Grathwohl et al., 2009), shown that ibuprofen is able to suppress RhoA activity in neuronal raising questions as to whether infl ammation may have an effect cells through PPARγ activation, promoting neurite elongation (Dill on neurodegeneration and cognitive decline rather than a direct et al., 2010). Therefore, PPARγ activation could be benefi cial in AD role on Aβ deposition. Furthermore, a study using two-photon at several levels. A recent prospective randomized, open-controlled microscopy in the intact brain of living AD mice has revealed an study with pioglitazone (a typical PPARγ agonist) has shown that involvement of microglia in neuron elimination, indicated by locally at 6 months the WMS-R logical memory-I scores signifi cantly increased number and migration velocity of microglia around lost increased in the pioglitazone group, but not in the control group neurons (Fuhrmann et al., 2010). Therefore, evidence has started (Hanyu et al., 2009). Another PPARγ agonist, rosiglitazone has been to accumulate that the function of microglia is neuroprotection in trialed with inconsistent results. In contrast to pioglitazone, rosigli- young individuals (by secretion of neurotrophic factors and anti- tazone cannot cross the blood brain barrier (BBB) (Festuccia et al., infl ammatory cytokines) and that “senescent” microglia contribute 2008) and it was suggested that the protective effects are mediated to the onset of sporadic AD (Streit et al., 2004, 2009). through its effects on insulin and glucocorticoids that are able to Similarly, there are other factors that may change the risk for AD penetrate into the brain. depending on the age, such as obesity or body mass index (BMI), Certain NSAIDs, such as fl urbiprofen and indomethacin, inhibit which is an important predictor for late life dementia. However, the nuclear translocation of the transcription factor NF-kB. In in late life, low and declining BMI is associated with increased addition, it was recently shown that R-fl urbiprofen can interfere AD risk. Therefore, there is time frame for the benefi cial effect of with the interaction between RXRα and 9-cis-retinoid acid, and certain factors, and since AD is a disease with a long preclinical that 9-cis-retinoid acid decreases (R)-fl urbiprofen’s reduction of period, trials of short duration in severe cases of AD do not provide Aβ secretion (You et al., 2009). R-fl urbiprofen has been shown to reliable information regarding development of AD (Bennett and upregulate NGF and BDNF in vitro, which could potentially offer Whitmer, 2009). neuroprotection (Zhao et al., 2008). However, as mentioned above, R-fl urbiprofen trials have not been successful, perhaps because of MULTIPLE MOLECULAR TARGETS FOR NSAIDs its low permeability into the brain and its weak pharmacological The type of NSAID appears to affect the outcome of the clinical activity (Imbimbo, 2009). trial (Figure 1). The inhibition of the canonical targets of NSAIDs, cyclooxygenase-1 and -2 (COX-1 and COX-2), do not seem to be DURATION AND DOSE responsible for the protective effect of NSAIDs in AD (see review The duration of the treatment could also infl uence the magni- Lleo et al., 2007). On the contrary, some COX-2 inhibitors may tude of the effect. A meta-analysis of nine studies revealed that raise Aβ1-42 secretion (Kukar et al., 2005). the benefi t of the NSAID treatment was greater in long-term users Interestingly, some NSAIDs and other small organic molecules than in intermediate users (Etminan et al., 2003). Moreover, it has have been found to modulate γ-secretase and to selectively reduce been suggested that at least 2 years of exposure are necessary to Aβ1-42 levels without affecting Notch cleavage. A subset of NSAIDs obtain full benefi t, so the benefi ts may be greater the longer NSAIDs including ibuprofen, sulidac sulfi de, and indomethacin have been are used (Sastre et al., 2006a). The effect of NSAIDs in mice has

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been reviewed extensively by Imbimbo (2009). Short term studies 2009). Similar positive effects in ApoE4 carriers have also been (3- to 7-days treatment) in transgenic mice revealed decreases in seen when the NSAIDs have been taken in conjunction with Vit E Aβ levels, particularly in the Aβ42 isoform and activated micro- (Fotuhia et al., 2008). In addition, the infl uence of NSAID use in glia, although some studies have shown no changes, depending microglia activation has been noted in all ApoE genotypes however on the drug and the animal model (Eriksen et al., 2003; Heneka the trend of lower counts of glial cells with regular NSAID use was et al., 2005; Lanz et al., 2005). Long-term administration has dem- more marked in patients carrying the ApoEε4/4 alleles (Alafuzoff onstrated protective effects predominantly using ibuprofen and et al., 2000). indomethacin treatments, in both types of Aβ, as well as brain By contrast, results from clinical trials with rosiglitazone suggest plaque load and infl ammation (see Imbimbo, 2009). However, that those without an APOE ε4 allele exhibit cognitive and func- chronic R-fl urbiprofen produced weak effects on Aβ deposition, tional improvement in response to rosiglitazone, while those that do and was more effective as a preventive rather than a therapeu- carry the allele carriers showed no improvement and some decline tic treatment (Kukar et al., 2007). This is in line with the results was noted (Risner et al., 2006). ApoE4 and C-terminal-truncated obtained in clinical trials using fl urbiprofen. fragments of apoE4 [apoE4(1–272), lacking the C-terminal 27 aa] The dose and permeability of the drug could be relevant, although impair cytoskeletal structure and mitochondrial function and its some epidemiological studies suggest that the daily dose is not seems that rosiglitazone reverses this effect. important. In’t Veld et al. (2001) noted that low doses had effects equal to those of the higher doses typically prescribed for osteoar- CONCLUSIONS thritis and other infl ammatory conditions. However, the failure of There is still controversy regarding the reasons why clinical tri- some clinical trials has been associated with the low permeability als with NSAIDs have provided such disappointing results. Here of certain drugs such as R-fl urbiprofen and rosiglitazone. In addi- we suggest that the short duration of the trials, the use of drugs tion, there is some confl ict between the potency of certain NSAIDs targeting the wrong molecule, the wrong timing of the treatment to decrease Aβ42 in vitro (reaching 300 µM) and the effective drug (patients too old or too severely ill), the low levels of the drugs concentration in the brain. Active concentrations of NSAIDs found reaching the CNS and the genetic variability of the patients may in human plasma and cerebrospinal fl uid are in the lower µM range all have contributed to the failures. (Bannwarth et al., 1990, 1995), which could not account for the It is still unclear whether NSAIDs are benefi cial because of effects on γ-secretase cleavage. Unfortunately, the clinical dose is their effects on reducing Aβ or whether it is because of their anti- limited because of adverse effects such as irritation and ulceration infl ammatory action or the interaction between both (reducing of the gastro-intestinal (GI) mucosa. There is growing interest in infl ammation may decrease Aβ generation and the other way improving absorption and BBB permeability of certain NSAIDs around). It would be helpful in the future to determine whether in order to allow the administration of lower doses of these drugs. patients involved in trials experience changes in biomarkers in Another point that has to be borne in mind is that the barrier may blood or CSF (such as Aβ levels, tau or infl ammatory markers) be compromised in neurodegenerative diseases, permitting the dif- and whether those correlate with cognitive performance. fusion of molecules that usually have no access to the brain paren- Taking all the currently available evidence together, NSAIDs chyma, therefore the dose reaching the brain can be different in AD should be used as preventive treatment rather than a therapeutic patients compared with healthy controls (Nguyen et al., 2002). option and this would make more sense in a disease with a long pre- clinical period, with evidence that microglial/cytokine events take ApoE GENOTYPE place years or even decades before plaques or tangles are detected Another possible confounding factor in NSAID trials is the geno- (Griffi n et al., 1989; Cagnin et al., 2001). type of the patients being treated, most notably in relation to ApoE. The majority of prospective studies appear to show greater benefi ts ACKNOWLEDGMENTS in those with an ApoE ε4 allele (Hayden et al., 2007; Szekely et al., We would like to thank Jonathan Cheung for his help in the design 2008b). In a recent trial, the ApoE ε4 carriers treated with ibuprofen of the fi gure and the Alzheimer’s Research Trust for their support were the only group without cognitive decline (Pasqualetti et al., (grants ART/PG2009/5 and ART/PPG2009B/10).

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of APOE and NSAID type. Neurology A subset of NSAIDs lower amy- tangles in a P301S tauopathy mouse cial relationships that could be construed 70, 17–24. loidogenic Abeta42 independently of model. Neuron 53, 337–351. as a potential confl ict of interest. Varvel, N. H., Bhaskar, K., Kounnas, M. cyclooxygenase activity. Nature 414, You, X., Zhang, Y. W., Chen, Y., Huang, Z., Wagner, S. L., Yang, Y., Lamb, B. 212–216. X., Xu, R., Cao, X., Chen, J., Liu, Received: 01 March 2010; paper pending T., and Herrup, K. (2009). NSAIDs Wyss-Coray, T. (2006). Inflammation Y., Zhang, X., and Xu, H. (2009). published: 22 March 2010; accepted: 24 April prevent, but do not reverse, neuronal in Alzheimer disease: driving force, Retinoid X receptor-alpha mediates 2010; published online: 18 May 2010. cell cycle reentry in a mouse model of bystander or benefi cial response? Nat. (R)-fl urbiprofen’s effect on the lev- Citation: Sastre M and Gentleman SM Alzheimer disease. J. Clin. Invest. 119, Med. 12, 1005–1015. els of Alzheimer’s beta-amyloid. J. (2010) NSAIDs: how they work and their 3692–3702. Wyss-Coray, T., Loike, J. D., Brionne, T. C., Neurochem. 111, 142–149. prospects as therapeutics in Alzheimer’s Vlad, S. C., Miller, D. R., Kowall, N. W., Lu, E., Anankov, R., Yan, F., Silverstein, Zhao, X., Rebeck, G. W., Hoe, H. S., and disease. Front. Ag. Neurosci. 2:20. doi: and Felson, D. T. (2008). Protective S. C., and Husemann, J. (2003). Adult Andrews, P. M. (2008). Tarenfl urbil 10.3389/fnagi.2010.00020 effects of NSAIDs on the development mouse astrocytes degrade amyloid- protection from cytotoxicity is asso- Copyright © 2010 Sastre and Gentleman. of Alzheimer disease. Neurology 70, beta in vitro and in situ. Nat. Med. 9, ciated with an upregulation of neu- This is an open-access article subject to 1672–1677. 453–457. rotrophins. J. Alzheimers Dis. 15, an exclusive license agreement between Weggen, S., Eriksen, J. L., Das, P., Sagi, S. Yoshiyama, Y., Higuchi, M., Zhang, B., 397–407. the authors and the Frontiers Research A., Wang, R., Pietrzik, C. U., Findlay, K. Huang, S. M., Iwata, N., Saido, T. C., Foundation, which permits unrestricted A., Smith, T. E., Murphy, M. P., Bulter, Maeda, J., Suhara, T., Trojanowski, J. Conflict of Interest Statement: The use, distribution, and reproduction in any T., Kang, D. E., Marquez-Sterling, N., Q., and Lee, V. M. (2007). Synapse authors declare that the report was written medium, provided the original authors and Golde, T. E., and Koo, E. H. (2001). loss and microglial activation precede in the absence of any commercial or fi nan- source are credited.

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