Mechanistic and therapeutic role of NLRP3 inflammasome in the pathogenesis of Alzheimer's disease

Alzheimer's disease (AD), a progressive neurodegenerative disorder, has emerged as the most common form of dementia in the elderly. Several pathological hallmarks have been identified, including neuroinflammation. A comprehensive insight into the underlying mechanisms that can fuel the development of novel therapeutic approaches is necessary because of the alarmingly rapid increase in the frequency of incidence. Recently, NLRP3 inflammasome was identified as a critical mediator of neuroinflammation. Activation of nucleotide‐binding domain (NOD)‐like receptor protein 3 (NLRP3) inflammasome by amyloid, neurofibrillary tangles, impaired autophagy and endoplasmic reticulum stress, triggers the release of pro‐inflammatory cytokines such as IL‐1β and IL‐18. Subsequently, these cytokines can promote neurodegeneration and cognitive impairment. It is well established that genetic or pharmacological ablation of NLRP3 alleviates AD‐related pathological features in in vitro and in vivo models. Therefore, several synthetic and natural compounds have been identified that exhibit the potential to inhibit NLRP3 inflammasome and alleviate AD‐associated pathology. The current review article will highlight the various mechanisms by which activation of NLRP3 inflammation occurs during Alzheimer's disease, and how it influences neuroinflammation, neurodegeneration and cognitive impairment. Moreover, we will summarise the different small molecules that possess the potential to inhibit NLRP3 and can pave the path for developing novel therapeutic interventions for AD. Alzheimer's disease (AD) is the most common form of dementia in the elderly and characterised by the accumulation of inflammatory molecules in the brain. Activation of NLRP3 inflammasome within the brain contributes towards inflammation and AD‐related cognitive dysfunction. NLRP3 activation within microglia leads to the activation of pro‐inflammatory IL‐1β and IL‐18. Inhibition of NLRP3 confers protection against AD‐related pathological features in different experimental models. Therefore, significant efforts have been made in identifying and developing pharmaceutical agents targeting NLRP3. It is highly anticipated that NLRP3 inhibition can pave the path for developing novel therapeutic interventions for AD.