Non-steroidal anti-inflammatory drugs and cyclooxygenase in Alzheimer's disease

Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference in the chronic inflammatory reaction, that takes place in AD. The best-characterized action of NSAIDs is the inhibition of cyclooxygenase (COX). There is special interest for anti-inflammatory treatment of AD using selective COX-2 inhibitors. These inhibitors reduce the inflammatory reaction but lack the side effects observed with non-selective NSAIDs. So far, clinical trials designed to inhibit inflammation or COX-2 activity have failed in the treatment of AD patients. Several lines of evidence can explain the failures of the anti-inflammatory and anti-COX-2 trials on AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in AD brain. Understanding the role of COX in AD pathogenesis could contribute to the development of an anti-inflammatory therapy for the treatment or prevention of AD.     

Genetically modified mice models for Alzheimer's disease

Transgenic mice models for Alzheimer's disease (AD) are essential to the understanding of disease pathophysiology, develop robust behavioral models and predict outcomes from pharmacological interventions. In the last 10 years, numerous mice models have been developed particularly focusing on the amyloid precursor protein-processing pathway and Tau pathology since brain amyloid deposits and Tau tangles are some of the primary neuropathological consequences of AD. Current views on the amyloid hypothesis and mice models relating to the role of soluble Abeta oligomers and intracellular Abeta in AD pathophysiology will be reviewed. Several novel transgenic mice models that have recently been developed and their potential impact on understanding disease pathogenesis will also be summarized.     

Exploring the role of COX-2 in Alzheimer's disease: Potential therapeutic implications of COX-2 inhibitors

This review highlights the potential role of cyclooxygenase-2 enzyme (COX-2) in the pathogenesis of Alzheimer's disease (AD) and the potential therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) in the management of AD. In addition to COX-2 enzymes role in inflammation, the formation of amyloid plaques and neurofibrillary tangles in the brain, the review emphasizes that COXs-2 have a crucial role in normal synaptic activity and plasticity, and have a relationship with acetylcholine, tau protein, and beta-amyloid (Aβ) which are the main causes of Alzheimer's disease. Furthermore, the review points out that COX-2 enzymes have a relationship with kinase enzymes, including Cyclin Dependent Kinase 5 (CDK5) and Glycogen Synthase Kinase 3β (GSK3β), which are known to play a role in tau phosphorylation and are strongly associated with Alzheimer's disease. Therefore, the use of drugs like NSAIDs may be a hopeful approach for managing AD.However, results from studies examining the effectiveness of NSAIDs in treating AD have been mixed and further research is needed to fully understand the mechanisms by which COX-2 and NSAIDs may be involved in the development and progression of AD and to identify new therapeutic strategies.     

Cyclo-oxygenase-2 inhibitors: rationale and therapeutic potential for Alzheimer's disease

The newly introduced cyclo-oxygenase-2 (COX-2) inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs) have been established as effective agents in treating arthritic conditions, while greatly reducing the gastrointestinal adverse effects of traditional NSAIDs. There are expectations that NSAIDs will be useful in the treatment of Alzheimer's disease (AD), and that COX-2 inhibitors might have a role. However, a recently reported clinical trial of a COX-2 inhibitor in AD indicated that it was neither protective nor did it accelerate the decline. The expectations were based on pathological evidence of inflammatory changes associated with AD lesions and epidemiological evidence of a reduced prevalence of AD in populations taking NSAIDs. They were supported by preliminary evidence showing efficacy of NSAIDs in treating patients with AD. These data are based on the use of traditional NSAIDs. Whether COX-2 inhibitors would be similarly effective was uncertain since COX-2 is constitutively expressed in neurons. Animal experiments suggest that COX-2 may be performing adaptive functions associated with normal neurons and protective functions associated with stressed neurons. These results emphasise that the appropriate target for NSAID trials in AD is COX-1, but they also indicate that there would be no contraindication to the use of those traditional NSAIDs which have mixed COX-1/COX-2 inhibiting activity.     

Role of the immune system in the pathogenesis,prevention and treatment of Alzheimer's disease

The dysregulation in the metabolism of beta-amyloid precursor protein and consequent deposition of amyloid-beta (Abeta) has been envisaged as crucial for the development of neurodegeneration in Alzheimer's disease (AD). Amyloid deposition begins 10-20 years before the appearance of clinical dementia. During this time, the brain is confronted with increasing amounts of toxic Abeta peptides and data from the last decade intriguingly suggest that both the innate and the adaptive immune systems may play an important role in the disorder. Innate immunity in the brain is mainly represented by microglial cells, which phagocytose and degrade Abeta. As the catabolism of Abeta decreases, glial cells become overstimulated and start to produce substances that are toxic to neurons, such as nitric oxide and inflammatory proteins. Pro-inflammatory cytokines can be directly toxic or stimulate Abeta production and increase its cytotoxicity. A therapeutic possibility arises from clinical studies, which demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) may delay the onset and slow the progression of AD. Recent data show that in addition to the suppression of inflammatory processes in the brain NSAIDs may decrease the production of Abeta peptides. The role of adaptive immunity lies mainly in the fact that Abeta can be recognised as an antigen. Immunisation with Abeta peptides and peripheral administration of Abeta-specific antibodies both decrease senile plaques and cognitive dysfunction in murine models of AD. A recent trial in humans seems still to be hampered by adverse effects. As adaptive immunity decreases with aging while innate immunity remains intact, immunotherapy for AD will have to be adapted to this situation. Strategies that combine vaccination and inflammatory drug treatment could be considered.     

COX-2 and Alzheimer's disease: potential roles in inflammation and neurodegeneration

Epidemiological and clinical data suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) are beneficial in the treatment and prevention of Alzheimer's disease (AD). NSAIDs act by inhibiting cyclooxygenase, an enzyme that occurs in constitutive and inducible isoforms, known respectively as COX-1 and COX-2. Recognition that COX-2 plays a key role in inflammation led to the hypothesis that COX-2 might represent the primary target for NSAIDs in AD, consistent with inflammatory processes occurring in AD brain. This review highlights recently gathered evidence leading to a more complex view of the role of COX-2 in AD, including evidence that COX-2 directly contributes to neuronal vulnerability. Consideration of these roles is critical for the rational implementation of NSAID therapy in AD.     

COX-2 and Alzheimer’s disease: potential roles in inflammation and neurodegeneration

Epidemiological and clinical data suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) are beneficial in the treatment and prevention of Alzheimer’s disease (AD). NSAIDs act by inhibiting cyclooxygenase, an enzyme that occurs in constitutive and inducible isoforms, known respectively as COX-1 and COX-2. Recognition that COX-2 plays a key role in inflammation led to the hypothesis that COX-2 might represent the primary target for NSAIDs in AD, consistent with inflammatory processes occurring in AD brain. This review highlights recently gathered evidence leading to a more complex view of the role of COX-2 in AD, including evidence that COX-2 directly contributes to neuronal vulnerability. Consideration of these roles is critical for the rational implementation of NSAID therapy in AD.     

Pathways of inflammatory activation in Alzheimer's disease: potential targets for disease modifying drugs

In the human brain several cell types are capable of initiating and amplifying a brain specific inflammatory response involving the synthesis of cytokines, prostaglandins and oxygen free radicals. In Alzheimer's disease (AD), signs of an inflammatory activation of microglia and astroglia are present inside and outside amyloid deposits. Cell culture and animal models suggest an interactive relationship between inflammatory activation, reduced neuronal functioning and deposition of amyloid. The activation of inflammation-associated enzymes such as p38 mitogen-activated protein kinase (p38 MAPK) and cycloxygenase-2 (COX-2) is not restricted to glial cells but also found in neurons and may contribute to intraneuronal damage. Epidemiological studies have shown a reduced risk of AD among users of anti-inflammatory drugs. Therefore, anti-inflammatory drugs have become the focus of several new treatment strategies. Small clinical trials with non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and diclofenac showed a trend for a disease modifying effect, while clinical trials with steroids did not show a beneficial effect. NSAIDs may not only act on COX-2 but also inhibit COX-1 activity or activate peroxisome proliferator-activated receptor gamma (PPAR gamma). Among promising new strategies to reduce the inflammatory activation in the CNS interfering with intracellular pro-inflammatory pathways has been shown to be effective in various cell culture and animal models. Inhibitors of p38MAPK and PPAR gamma agonists may be suitable agents to suppress inflammatory activation in AD.     

Emerging beta-amyloid therapies for the treatment of Alzheimer's disease

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD is defined pathologically by extracellular neuritic plaques comprised of fibrillar deposits of beta-amyloid peptide (Abeta) and neurofibrillary tangles comprised of paired helical filaments of hyperphosphorylated tau. Current therapies for AD, such as cholinesterase inhibitors, treat the symptoms but do not modify the progression of the disease. The etiology of AD is unclear. However, data from familial AD mutations (FAD) strongly support the "amyloid cascade hypothesis" of AD, i.e. that neurodegeneration in AD is initiated by the formation of neurotoxic beta-amyloid (Abeta) aggregates; all FAD mutations increase levels of Abeta peptide or density of Abeta deposits. The likely link between Abeta aggregation and AD pathology emphasizes the need for a better understanding of the mechanisms of Abeta production. This review summarizes current therapeutic strategies directed at lowering Abeta levels and decreasing levels of toxic Abeta aggregates through (1) inhibition of the processing of amyloid precursor protein (APP) to Abeta peptide, (2) inhibition, reversal or clearance of Abeta aggregation, (3) cholesterol reduction and (4) Abeta immunization.     

Always around, never the same: pathways of amyloid beta induced neurodegeneration throughout the pathogenic cascade of Alzheimer's disease

There is an increasing amount of evidence showing the importance of intermediate aggregation species of amyloid beta (Abeta) in the pathogenic cascade of Alzheimer's disease (AD). Different Abeta assembly forms may mediate diverse toxic effects at different stages of the disease. Mouse models for AD suggest that intraneuronal accumulation of Abeta oligomers might be involved in AD pathogenesis at a very early stage of the disease. The detrimental effect of oligomeric Abeta on synaptic efficacy is suggested to be an early event in the pathogenic cascade. Also early neuronal responses as activation of the unfolded protein response are processes likely to be associated with the increased occurrence of oligomeric or low fibrillar Abeta in AD pathology. In later stages of AD pathology, the fibrillarity of Abeta increases, concomitantly with a neuroinflammatory response, followed by tau related neurofibrillary changes in end stage pathology. We will review recent findings in in vitro cell models, in vivo mouse models, and post mortem AD brain tissue in view of the effects of different Abeta peptide species on neurodegeneration during AD pathogenesis. Insight into the role of different Abeta species during AD pathogenesis is essential for the development of disease modifying drugs and therapeutical strategies.     

Effects of S-2474, a novel nonsteroidal anti-inflammatory drug, on amyloid beta protein-induced neuronal cell death

1. The accumulation of amyloid beta protein (Abeta) in the brain is a characteristic feature of Alzheimer's disease (AD). Clinical trials of AD patients with nonsteroidal anti-inflammatory drugs (NSAIDs) indicate a clinical benefit. NSAIDs are presumed to act by suppressing inhibiting chronic inflammation in the brain of AD patients. 2. In the present study, we investigated effects of S-2474 on Abeta-induced cell death in primary cultures of rat cortical neurons. 3. S-2474 is a novel NSAID, which inhibits cyclo-oxygenase-2 (COX-2) and contains the di-tert-butylphenol antioxidant moiety. S-2474 significantly prevented neurons from Abeta(25 - 35)- and Abeta(1 - 40)-induced cell death. S-2474 ameliorated Abeta-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA completely. 4. Prior to cell death, Abeta(25 - 35) generated prostaglandin D(2) (PGD(2)) and free radicals from neurons. PGD(2) is a product of cyclo-oxygenase (COX), and caused neuronal cell death. 5. S-2474 significantly inhibited the Abeta(25 - 35)-induced generation of PGD(2) and free radicals. 6. The present cortical cultures contained little non-neuronal cells, indicating that S-2474 affected neuronal survival directly, but not indirectly via non-neuronal cells. Both an inhibitory effect of COX-2 and an antioxidant effect might contribute to the neuroprotective effects of S-2474. 7. In conclusion, S-2474 exhibits protective effects against neurotoxicity of Abeta. Furthermore, the present study suggests that S-2474 may possess therapeutic potential for AD via ameliorating degeneration in neurons as well as suppressing chronic inflammation in non-neuronal cells.     

The role of COX-1 and COX-2 in Alzheimer's disease pathology and the therapeutic potentials of non-steroidal anti-inflammatory drugs

Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference of the chronic inflammatory reaction in AD. The best-characterised action of NSAIDs is the inhibition of cyclooxygenase (COX). So far, clinical trials designed to inhibit inflammation or cyclooxygenase activity have failed in the treatment of AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in neurodegeneration and AD pathogenesis. Understanding the pathological, physiological and neuroprotective role of cyclooxygenase will contribute to the development of a therapy for the treatment or prevention of AD.     

NSAIDs: small molecules for prevention of Alzheimer's disease or precursors for future drug development?

Non-steroidal anti-inflammatory drugs (NSAIDs) have been considered for treatment and prevention of Alzheimer's disease (AD) for more than two decades. Biochemical markers in the brains of individuals with AD suggest that inflammation might be a driving cause of the disease that can be suppressed by drug treatment. In addition, a subgroup of widely used NSAIDs inhibits generation of the pathogenic amyloid-beta(1-42) peptide (Abeta42) independently of the inflammatory cyclooxygenase (COX) pathway. Here, we summarize evidence showing that the efficacy of NSAIDs in AD might be attributable to either anti-inflammatory or anti-amyloidogenic activities, and we acknowledge the possibility that current NSAIDs could be neuroprotective through synergistic mechanisms. Ongoing drug development efforts are concentrating on improvement of the COX-independent Abeta42-lowering activity to prevent amyloid pathology and secondary inflammatory reactions and to avoid the clinical side-effects associated with inhibition of COX.     

Anti-inflammatory drugs: a hope for Alzheimer’s disease?

Human brain cells are capable of initiating and amplifying a brain specific inflammatory response involving the synthesis of cytokines, acute-phase proteins, complement proteins, prostaglandins and oxygen radicals. In Alzheimer’s disease (AD), all signs of an inflammatory microglial and astroglial activation are present inside and outside amyloid depositions and along axons of neurones with neurofibrillary tangles. Cell culture and animal models suggest a bidirectional relationship between inflammatory activation of glial cells and the deposition of amyloid. Although it remains unclear which of the different pathophysiological processes in AD may be the driving force in an individual case, the inflammatory activation may increase the speed of cognitive decline. Epidemiological studies point to a reduced risk of AD among users of anti-inflammatory drugs. Therefore, anti-inflammatory drugs have become the focus of several new treatment strategies. A clinical trial with the non-steroidal anti-inflammatory drug (NSAID) indomethacin showed promising results, while a clinical trial with steroids did not show a beneficial effect. Further trials with NSAIDs such as unselective cyclooxygenase (COX) and selective cyclooxygenase-2 (COX-2) inhibitors are on their way. COX inhibitors may not only act on microglial and astroglial cells but also reduce neuronal prostaglandin production. New data suggest that prostaglandins enhance neurotoxicity or induce pro-inflammatory cytokine synthesis in astroglial cells. Amongst these promising new strategies to reduce microglial or monocyte activation, interfering with intracellular pathways has been shown to be effective in various cell culture and animal models but clinical studies have not yet been performed.     

Anti-inflammatory drugs: a hope for Alzheimer's disease?

Human brain cells are capable of initiating and amplifying a brain specific inflammatory response involving the synthesis of cytokines, acute-phase proteins, complement proteins, prostaglandins and oxygen radicals. In Alzheimer's disease (AD), all signs of an inflammatory microglial and astroglial activation are present inside and outside amyloid depositions and along axons of neurones with neurofibrillary tangles. Cell culture and animal models suggest a bidirectional relationship between inflammatory activation of glial cells and the deposition of amyloid. Although it remains unclear which of the different pathophysiological processes in AD may be the driving force in an individual case, the inflammatory activation may increase the speed of cognitive decline. Epidemiological studies point to a reduced risk of AD among users of anti-inflammatory drugs. Therefore, anti-inflammatory drugs have become the focus of several new treatment strategies. A clinical trial with the non-steroidal anti-inflammatory drug (NSAID) indomethacin showed promising results, while a clinical trial with steroids did not show a beneficial effect. Further trials with NSAIDs such as unselective cyclooxygenase (COX) and selective cyclooxygenase-2 (COX-2) inhibitors are on their way. COX inhibitors may not only act on microglial and astroglial cells but also reduce neuronal prostaglandin production. New data suggest that prostaglandins enhance neurotoxicity or induce pro-inflammatory cytokine synthesis in astroglial cells. Amongst these promising new strategies to reduce microglial or monocyte activation, interfering with intracellular pathways has been shown to be effective in various cell culture and animal models but clinical studies have not yet been performed.     

Ibuprofen suppresses interleukin-1beta induction of pro-amyloidogenic alpha1-antichymotrypsin to ameliorate beta-amyloid (Abeta) pathology in Alzheimer's models.

Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (Abeta) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Abeta production has not been ruled out. We show that ibuprofen reduced Abeta brain levels in rats from exogenously infused Abeta in the absence of altered Abeta production. To determine whether ibuprofen inhibits pro-amyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Abeta and inflammation-related molecules alpha1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor gamma) (PPARgamma) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1beta, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Abeta42 production, these observations suggest that ibuprofen reduction of Abeta pathology may not be mediated by altered Abeta42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1beta and its downstream target ACT).     

The potential role of non-steroidal anti-inflammatory drugs in treating Alzheimer's disease

Epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Despite encouraging evidence, all large, long-term, placebo-controlled clinical trials aimed at reducing inflammation in the brain of AD patients produced negative results. More recently it has been shown that some NSAIDs decrease the production of amyloid-beta(1-42) (Abeta42), the major component of senile plaques of the AD brain, and counteract the progression of Abeta42 pathology in transgenic mouse models of AD. The proposed mechanism for this activity is an allosteric modulation of gamma-secretase activity, the enzyme responsible for the formation of amyloid-beta. The inhibition of Abeta42 production is independent from the anti-cyclooxygenase (COX) activity and is related to the chemical structure of the compounds, with some NSAIDs being active (ibuprofen, sulindac, flurbiprofen, indomethacin, diclofenac) and others not (naproxen, aspirin, celecoxib). This could explain the negative results of the large AD trials carried out so far, as they were conducted with compounds (naproxen, hydroxychloroquine, dapsone, prednisone, rofecoxib and celecoxib) that are not able to decrease Abeta42 production. Unfortunately, the use of these NSAIDs in AD is hampered by a significant gastrointestinal toxicity associated with COX inhibition. Thus, new NSAID analogues are being developed with potent and selective inhibitory activity on Abeta42 but with either lack of COX inhibitory activity or reduced gastrointestinal toxicity potential.     

Amyloidosis and Alzheimer's disease

Alzheimer's disease (AD) is the most frequent type of amyloidosis in humans and the commonest form of dementia. Extracellular Abeta amyloid deposits in the form of amyloid plaques and cerebral amyloid angiopathy as well as intraneuronal neurofibrillary tangles co-exist in the brain parenchyma of AD patients, the cognitive areas being the most severely affected. This review focuses on the potential role of amyloid in the development of neurodegeneration and presents studies of AD and other unrelated inherited dementia syndromes associated with neuronal loss and amyloid deposition in the brain.     

Disease-modifying therapies in Alzheimer's disease: how far have we come?

Currently, there are no disease-modifying therapies available for Alzheimer's disease (AD). Acetylcholinesterase inhibitors and memantine are licensed for AD and have moderate symptomatic benefits. Epidemiological studies have suggested that NSAIDs, estrogen, HMG-CoA reductase inhibitors (statins) or tocopherol (vitamin E) can prevent AD. However, prospective, randomised studies have not convincingly been able to demonstrate clinical efficacy. Major progress in molecular medicine suggests further drug targets.The metabolism of the amyloid-precursor protein and the aggregation of its Abeta fragment are the focus of current studies. Abeta peptides are produced by the enzymes beta- and gamma-secretase. Inhibition of gamma-secretase has been shown to reduce Abeta production. However, gamma-secretase activity is also involved in other vital physiological pathways. Involvement of gamma-secretase in cell differentiation may preclude complete blockade of gamma-secretase for prolonged times in vivo. Inhibition of beta-secretase seems to be devoid of serious adverse effects according to studies with knockout animals. However, targeting beta-secretase is hampered by the lack of suitable inhibitors to date. Other approaches focus on enzymes that cut inside the Abeta sequence such as alpha-secretase and neprilysin. Stimulation of the expression or activity of alpha-secretase or neprilysin has been shown to enhance Abeta degradation. Furthermore, inhibitors of Abeta aggregation have been described and clinical trials have been initiated. Peroxisome proliferator activated receptor-gamma agonists and selected NSAIDs may be suitable to modulate both Abeta production and inflammatory activation. On the basis of autopsy reports, active immunisation against Abeta in humans seems to have proven its ability to clear amyloid deposits from the brain. However, a first clinical trial with active vaccination against the full length Abeta peptide has been halted because of adverse effects. Further trials with vaccination or passive transfer of antibodies are planned.     

Radioligand development for PET imaging of beta-amyloid (Abeta)--current status

Two of the main pathological hallmarks of Alzheimer's disease (AD) are neuritic plaques and neurofibrillary tangles. Significant evidence supports a critical and probable causative role of beta amyloid (Abeta) plaque formation. Since neuroprotective treatments are typically most effective at early stages of injury, the detection and measurement of Abeta load in living brain should be performed at early and perhaps even presymptomatic stages of AD. Two primary targets of molecular imaging research with positron emission tomography (PET) are to develop surrogate markers (radioligands) for assessing disease progression and for monitoring the efficacy of developmental therapeutics. Here, we review the current status of radioligand development for PET imaging of Abeta aggregates. General structure-activity relationships have emerged, including the identification of at least three different ligand binding sites in various Abeta aggregates and recognition of the general structural requirements for ligand binding at each site. Also a few radioligands applicable to imaging Abeta plaques in living human brain with positron emission tomography (PET) have emerged, including [(11)C]PIB, [(11)C]SB-13 and [(18)F]FDDNP.