The NLRP3-P2X7 Axis and Cytokine Crosstalk in Alzheimer's Disease: Mechanisms, Implications, and Therapeutic Opportunities.

Abstract

Alzheimer's disease (AD) is the primary cause of dementia in elderly individuals, characterized by progressive memory loss, cognitive decline, and impaired daily functioning. Pathologically, AD is associated with the accumulation of amyloid-β (Aβ) plaques, tau tangles, mitochondrial dysfunction, and chronic neuroinflammation. The activation of the NOD-like receptor pyrin domain- containing 3 (NLRP3) inflammasome by Aβ clusters triggers microglial activation, leading to a cascade of inflammatory responses. Similarly, tau tangles stimulate neuronal and glial cells, further amplifying NLRP3 activation and perpetuating a cycle of chronic inflammation. Mitochondrial dysfunction exacerbates this process by increasing oxidative stress and inflammasome activation. Additionally, purinergic receptor P2X7 (P2X7R) activation in microglia plays a crucial role in initiating neuroinflammation, making it a potential therapeutic target. Despite extensive research, current AD therapies remain symptomatic rather than disease-modifying. Targeting the NLRP3 inflammasome offers a promising strategy for mitigating AD progression. Various small-molecule inhibitors, monoclonal antibodies, and repurposed drugs have been explored to inhibit NLRP3 activation and its downstream signaling pathways. Preclinical studies suggest that NLRP3 inhibitors effectively reduce Aβ- and tau-induced neuroinflammation while improving mitochondrial function and overall neuronal survival. This review summarizes NLRP3 inflammasome priming, activation, and the therapeutic potential of its inhibitors in AD, highlighting challenges such as tau pathology, biomarker limitations, and treatment optimization. While NLRP3 remains a promising target, most inhibitors are in the early stages with uncertain long-term efficacy and BBB penetration. Future research should explore genetic variability, sex differences, and alternative approaches to enhance neuroprotective strategies.