An important pathologic hallmark of Alzheimer’s disease (AD) is neuroinflammation, a process characterized in AD by disproportionate activation of cells (microglia and astrocytes, primarily) of the non-specific innate immune system within the CNS.
While inflammation itself is not intrinsically detrimental and deposition of the β-amyloid (Aβ) protein is considered to be the primary event in the pathogenesis of AD, a delicate balance of pro- and anti-inflammatory signals must be maintained to ensure that long-term exaggerated responses do not damage the brain over time.
Therefore, anti-inflammatory agent such as non-steroidal anti-inflammatory drugs (NSAIDs) have been considered as a potential treatment to prevent the onset and progression of the disease.
(Therapeutic implications of the prostaglandin pathway in Alzheimer's disease, 2014)
Inflammation in Alzheimer’s disease
Inflammation is a response to eliminate both the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult. If tissue health is not restored, inflammation becomes a chronic condition that continuously erodes the surrounding tissues.
In this type of inflammation, tissue injury and healing proceed simultaneously. The lateral damage normally caused tends to accumulate slowly, sometimes even asymptomatically during years. This can lead to severe tissue deterioration.
The characteristic inflammatory features such as swelling, heat, and pain are not present in the brain, and therefore we refer here to chronic instead of acute inflammation.
A characteristic feature of chronic inflamed tissues is the presence of an increased number of monocytes, as well as monocyte-derived tissue macrophages, that is microglia cells in the central nervous system (CNS). Inflammation clearly occurs in pathologically vulnerable regions of the AD brain, with increased expression of acute phase proteins and proinflammatory cytokines which are hardly evident in the normal brain.
Microglia, astrocytes, and neurons are responsible for the inflammatory reaction.
Activated cells strongly produce inflammatory mediators such as proinflammatory cytokines, chemokines, macrophage inflammatory proteins, monocyte chemo-attractant proteins, prostaglandins, leukotrienes, thromboxanes, coagulation factors, reactive oxygen species (and other radicals), nitric oxide, complement factors, proteases, protease inhibitors, pentraxins, and C-reactive protein.
The hypothesis is that the intractable nature of the Aβ plaques and tangles stimulates a chronic inflammatory reaction to clear this debris. These plaques contain dystrophic neurites, activated microglia, and reactive astrocytes. Aggregated amyloid fibrils and inflammatory mediators secreted by microglial and astrocytic cells contribute to neuronal dystrophy. Chronically activated glia can, furthermore, kill adjacent neurons by releasing highly toxic products such as reactive oxygen intermediates, nitric oxide (NO), proteolytic enzymes, complementary factors, or excitatory amino acids.
Inflammatory mediators and a number of stress conditions, in turn, enhance Amyloid Precursor Protein (APP) production and the amyloidogenic processing of APP to induce amyloid-β-42 (Aβ-42) peptide production. These circumstances also inhibit the formation of soluble APP fraction that has a neuronal protective effect. On the other hand, Aβ induces the expression of proinflammatory cytokines in glia cells in a vicious cycle, the activation of the complement cascade, and the induction of inflammatory enzyme systems such as the inducible nitric oxide synthase (iNOS) and the cyclooxygenase enzyme (COX)-2. Several lines of evidence suggest that all of these factors can contribute to neuronal dysfunction and cell death, either alone or in concert .
(A review: inflammatory process in Alzheimer's disease, role of cytokines, 2012)
(To be or not to be (inflamed) – is that the question in anti-inflammatory drug therapy of neurodegenerative disorders?, 2005)
The biosynthesis of inflammatory mediators, such as prostaglandins (PG), are catalysed by cyclo-oxygenase (COX) enzymes known as COX-1 and -2. In the brain PGs are produced by glial cells and by neurons and, when released extracellularly, act on G protein-coupled receptors (GPCRs) to induce an inflammatory response.
The biochemical profiles of COX-1 and -2 are distinctly different and, in general, COX-1 is constitutively expressed while COX-2 is mitogen induced. Cyclo-oxygenase-2 mRNA rises rapidly in response to a variety of inflammatory triggers, including Aβ, and it is thought to contribute to the disproportionate inflammatory response in AD.
An alternative pathogenic role for COX-2 relates to the observation that induction of COX-2 can result in the generation of highly reactive oxygen species, which can damage lipids, proteins and DNA. In AD, the expression of COX-2, but not COX-1, is increased in both the frontal cortex and in CA1 neurons that are destined for apoptotic cell death. Therefore, it is possible that COX-2 expression is involved in the early mechanisms leading to apoptotic cell death in AD.
(Alzheimer's disease and inflammation: a review of cellular and therapeutic mechanisms, 2000)
Mechanism of drug action
NSAIDs and the brain
It is presumed that the epidemiological beneficial effects of NSAID in AD are due to a reduction in the inflammatory response, especially of microglia and astrocytes, and a reduction in COX-2 expression by neurons, although the effects may be more direct.
For instance, many NSAIDs and structurally related compounds directly target gamma secretase (a membrane-associated multimeric protein complex that includes the aspartyl protease presenilin). Mutations in presenilin 1 and 2 are a well-known cause of familial AD. The gamma secretase complex differentially cleaves the transmembrane protein substrate APP, subsequently releasing Aβ. Select NSAIDs inhibit gamma secretase activity, and therefore reduce formation and accumulation of Aβ in animal models and human trials.
(Therapeutic Implications of the Prostaglandin Pathway in Alzheimer’s Disease, 2014)
NSAIDs may also function by activating the peroxisomal proliferators-activated receptors (PPARs), a group of nuclear hormone receptors that act to negatively inhibit the transcription of proinflammatory genes.
(A review: inflammatory process in Alzheimer's disease, role of cytokines, 2012)
Clinical evidence
Observational studies support the use of NSAIDs for prevention of AD, but RCT do not. Well-designed studies and innovative approaches are required to illuminate the exact relationship between NSAID use and AD risk. The appropriate dosage and duration of use to benefit and the safety are also needed to determine.
(Anti-inflammatory drugs and risk of Alzheimer's disease: an updated systematic review and meta-analysis, 2015)
NSAIDs (traditional NSAIDs and selective COX-2 inhibitors) do not slow down the decline in cognitive function in AD patients and do not improve non-cognitive and behavioural outcome measures such as depression, behavioral disturbance, activity of daily living, quality of life, clinical global impression of change and caregiver burden.
There is a wealth of epidemiological data supporting a role for anti-inflammatory treatment in the protection against the development of cognitive dysfunction. In addition, a role for inflammatory processes in the pathogenesis of AD is now widely recognised. Nevertheless, such data has not been translated into clinical benefit to patients with AD. Anti-inflammatory drugs do not seem, based on current evidence, to achieve any noticeable improvement in any of the various outcomes assessed, and foremost among them cognitive measures.
It cannot be discounted that most, in fact all of the studies assessing the efficacy of anti-inflammatory agents have been for a relatively short duration not usually exceeding 12 months. Further, patients selected are likely to have well established disease. It is accepted that the disease pathological process begins many years before the start of any symptoms associated with AD. Hence, one cannot comment on any potential efficacy for anti-inflammatories such as NSAIDs in those with very early stages of asymptomatic and silent disease. In fact epidemiological studies showing a benefit for anti-inflammatories has tended to assess patients with mainly rheumatological disorders on long term treatment with anti-inflammatory drugs. This may explain the discrepancy between the widely observed data from epidemiological studies and RCTs.
It is tempting to speculate whether a potential difference may exist between traditional NSAIDs and selective COX-2 inhibitors. It remains unclear whether this may relate to mechanism of action beyond COX-2 inhibition. In recent years more interest has been directed at selective COX-2 inhibitors, in part, due to the earlier perceived supremacy of this class of NSAIDs when it comes to side effects. In recent years, however, the benefit/risk profile of these drugs has been evaluated and earlier enthusiasm about their use has been critically reassessed. It will be of benefit that future work continues to include traditional NSAIDs as well as the newer COX-2 inhibitors.
(Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease, 2012)
Other possibilities
While further research regarding the therapeutic role of NSAIDs in AD is needed, the prostaglandin pathway may still represent a target for more selective drugs in the treatment of the disease.
Of the five prostaglandins, PGE 2 is the major effector in the CNS based on synthase expression data and direct measurements and is the most studied with regard to neuroinflammation. PGE 2 can effect a multitude of functional outcomes, owing its diverse signaling repertoire to the activation of four cell-surface GPCR subtypes, EP1, EP2, EP3, and EP4.
In EP1 knockout mouse models expressing both Swedish APP and PS1 mutations, which were identified in human familial AD, amyloid plaque burden was significantly reduced and these mice, when exposed to ischemia were shown to have less neuronal injury and lower secretion of proinflammatory cytokines, TNFα and IL-6, than their WT counterparts.
These data support EP1 as a potential therapeutic target for AD, and a highly selective antagonist as a potential effector.
(Therapeutic implications of the prostaglandin pathway in Alzheimer's disease, 2014)
Conclusions
Unfortunately, while numerous large-scale epidemiological and observational studies have identified a reduced risk of AD in patients who consume anti-inflammatory medications for chronic inflammatory diseases such as rheumatoid arthritis, randomized clinical trials failed to show a significant difference between the placebo and the treatment group.
Future clinical trials need to investigate further about the prophylactic role of anti-inflammatories, as NSAIDs may protect against the development of AD, while the appropriate dose, duration, and ratios of risk to benefit are still unclear.
