Microglia as a cellular target of diclofenac therapy in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an untreatable cause of dementia, and new therapeutic approaches are urgently needed. AD pathology is defined by extracellular amyloid plaques and intracellular neurofibrillary tangles. Research of the past decades has suggested that neuroinflammation plays a critical role in the pathophysiology of AD. This has led to the idea that anti-inflammatory treatments might be beneficial. Early studies investigated non-steroidal anti-inflammatory drugs (NSAIDS) such as indomethacin, celecoxib, ibuprofen, and naproxen, which had no benefit. More recently, protective effects of diclofenac and NSAIDs in the fenamate group have been reported. Diclofenac decreased the frequency of AD significantly compared to other NSAIDs in a large retrospective cohort study. Diclofenac and fenamates share similar chemical structures, and evidence from cell and mouse models suggests that they inhibit the release of pro-inflammatory mediators from microglia with leads to the reduction of AD pathology. Here, we review the potential role of diclofenac and NSAIDs in the fenamate group for targeting AD pathology with a focus on its potential effects on microglia.

Keywords: Alzheimer’s disease; NLRP3 inflammasome; NSAID; diclofenac; microglia; neuroinflammation.

Figure 1.

Chemical structures of meclofenamic acid and diclofenac. Prepared with JChemPaint.

Figure 2.

Proposed mechanisms of action for diclofenac in AD in the CNS and the periphery. Multiple pathways have been described for diclofenac that could potentially have therapeutic effects in AD. (1) Inhibition of COX-1 (primarily in microglia), COX-2 (primarily in neurons). (2) Inhibition of NLRP3 and release of IL-1β from microglia. (3) Potassium channel modulation in glia cells with inhibitory effect on inflammatory responses. (4) Inhibition of APP processing and Aβ plaque formation. (5) Inhibition of Specificity Protein 1 (SP1), a zinc-finger transcription factor regulating the transcription of APP, MAPT, BACE1, and CDK5 in the brain. (6) TNFα inhibition. (7) Inhibition of systemic inflammation and secondary neuroinflammation. Green errors = activation. Red errors = inhibition. Prepared with BioRender. Please see text for more details on abbreviations and the proposed mechanisms.