The hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative disease, include tau tangles, amyloid-β (Aβ) plaques, cognitive impairment, and severe neuroinflammation. A key molecular mediator linking immunological activation and neurological pathology in AD is the NLRP3 inflammasome. This review explains the intricate role of the NLRP3 inflammasome in AD, including its structure, activation mechanisms, and regulatory signaling pathways. The pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) that activate NLRP3 include oxidative stress, Aβ, mitochondrial dysfunction, ion fluxes, gut dysbiosis, and mitochondrial malfunction. Pro-inflammatory cytokines IL-1β and IL-18 are released when the inflammasome assembles with ASC and procaspase-1, leading to caspase-1 activation and pyroptosis. The article investigates both canonical and noncanonical pyroptosis pathways and provides detailed insights into how glial cells-specifically microglia and astrocytes-are involved in NLRP3-mediated neuroinflammation. It has been demonstrated that NLRP3 activation is modulated by several receptor-mediated signaling pathways, including NF-κB, TLR4, TREM2, purinergic, and MAP4K6, which intensify inflammatory responses in the AD brain. Furthermore, the review assesses preclinical and clinical research targeting NLRP3 and its upstream regulators, emphasizing potential treatment options as Simufilam, MCC950, OLT1177, and CY-09. This work highlights the therapeutic potential of the inflammasome and promotes the development of targeted anti-inflammatory treatments to ameliorate AD pathology by elucidating the molecular mechanisms linking NLRP3 to AD progression.
Chaudhary et al. (2026) studied this question.