The P2X7R-NLRP3 inflammasome axis in Alzheimer’s disease and therapeutic potential of synthetic and plant-derived natural compounds: A review

Abstract

Alzheimer’s disease is a prevalent neurodegenerative disease that is characterized by synaptic dysfunction followed by neuronal loss. The core pathological mechanisms of Alzheimer’s disease include the extracellular deposition of amyloid beta (Αβ) plaques and intracellular neurofibrillary tangle deposits inside the brain. These pathological hallmarks initiate the activation of neuro-immunological pathways that lead to neuronal loss. Aβ aggregation and neurofibrillary tangles function as danger signals and cause the release of extracellular adenosine-5'-triphosphate (ATP) from stressed or damaged neurons. The released ATP further amplifies the neuroinflammatory response by activating the P2X7 receptor (P2X7R) on microglial cells, which in turn facilitates NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complex formation and activation. The latter event leads to caspase-1 activation-mediated release of cytokines, including interleukin-1β and interleukin-18, followed by pyroptotic cell death. Consequently, this neuroinflammatory cascade results in cognitive impairment. Despite intensive research efforts, direct therapeutic targeting of the P2X7R has yielded limited clinical success, partly due to receptor compensatory mechanisms and genetic polymorphisms that affect treatment responsiveness. In this context, emerging evidence highlights the potential of targeting the downstream NLRP3 inflammasome via natural bioactive compounds or synthetic molecules as a more promising therapeutic strategy for modulating the neuroinflammatory pathways underlying Alzheimer’s pathogenesis. Collectively, this review summarizes the progressive molecular events linking Αβ and tau pathology to neuroinflammation via the P2X7R-NLRP3 inflammasome axis, while underscoring the therapeutic potential of plant-derived bioactive compounds as well as synthetic molecules in mitigating the progression of Alzheimer’s disease.