Pyroptosis in Alzheimer's disease: Mechanisms and neuroinflammatory networks.

Microglial dysfunction and NLRP3 inflammasome signaling in Alzheimer’s disease: mechanistic insights into neuroinflammation and neurodegeneration

Alzheimer's disease (AD) is a progressively debilitating neurodegenerative condition characterized by the accumulation of amyloid-β (Aβ), tau pathology, synaptopathy, and neuron loss. Recent studies suggest that Neuroinflammation is a critical part of the disease process rather than an accompanying feature of the mentioned pathological changes. Microglia, the immune cells of the central nervous system, respond to amyloid-beta and pathological tau and exhibit functional alterations leading to the transition from their initial anti-inflammatory and neuroprotective function to chronic inflammation. Persistent activation of microglia is linked with the inability to clear abnormal proteins, excessive complement-dependent synaptic loss, secretion of cytokines, activation of astrocytes, and neuronal damage. Various inflammatory pathways play their roles, and one of the most prominent is the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. The activation of the NLRP3 inflammasome leads to the recruitment of apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1 activation, followed by interleukin-1β (IL-1β) and IL-18 maturation and gasdermin D (GSDMD) cleavage, contributing to pyroptosis and inflammatory processes. The current review will cover changing role of microglia in AD progression, interactions between Aβ, tau, and inflammatory signaling pathways as well as molecular mechanisms of NLRP3 Inflammasome activation. Furthermore, it will discuss new approaches that could be used for modulations of NLRP3 inflammasome signaling, including selective small molecule inhibition, caspase-1 targeting, natural compound use, repurposed drugs, and new drug delivery systems. Specifically, the ability to cross blood-brain barrier (BBB), safety, translational challenges, and dissimilarity between animal models and humans' AD will be discussed in this context. Overall, targeting dysregulated Neuroinflammation, including NLRP3 inflammasome activation, could serve as an alternative approach to existing protein-directed treatment methods.

Targeting cytokine-driven neuroinflammation in Alzheimer's disease: mechanistic insights and pharmacological strategies.

The Role of Neuroinflammation in Alzheimer's Disease: Molecular Mechanisms and Emerging Therapeutic Approaches

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder traditionally characterized by amyloid-beta (Aβ) accumulation, tau pathology, synaptic dysfunction, and neuronal loss. Increasing evidence indicates that neuroinflammation is not merely a secondary consequence of neurodegeneration but an important component of AD pathogenesis. This review examines the molecular and cellular mechanisms through which neuroinflammation contributes to the progression of AD, with particular emphasis on microglial activation, TREM2 and soluble TREM2 (sTREM2) signaling, NLRP3 inflammasome activation, astrocyte–microglia interactions, and blood–brain barrier dysfunction. The review further evaluates emerging therapeutic strategies aimed at modulating these pathways, including NLRP3 inhibition, TREM2/sTREM2-targeted approaches, restoration of glial homeostasis, cytokine modulation, and pro-resolving strategies. Current evidence suggests that inflammatory responses may exert both protective and detrimental effects depending on disease stage, duration, and cellular context. Consequently, broad suppression of neuroinflammation may be insufficient and potentially counterproductive. Future therapeutic development may benefit from precision immunomodulation guided by disease-stage-specific biomarkers and molecular profiling. Understanding the complex interactions between neuroinflammation, pathological protein accumulation, glial dysfunction, and neurovascular abnormalities may therefore provide new opportunities for developing disease-modifying approaches to Alzheimer’s disease.

Microglia-mediated neuroinflammation in Alzheimer’s disease: mechanisms and emerging therapeutic targets

A “cellular state–pathological network–therapeutic window” framework is proposed and the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback are systematically discussed.

Targeting the NLRP3 Inflammasome in Alzheimer's Disease: Mechanistic Insights and Therapeutic Advances.

Alzheimer's disease (AD) is the leading cause of dementia, yet current therapies provide limited clinical benefit. Neuroinflammation, as an early and sustained driver of AD, places the NLRP3 inflammasome at the center of pathological and therapeutic focus. In this review, we synthesize recent advances in the structure, assembly, and activation of the NLRP3 inflammasome, and evaluate its contribution to AD using evidence from human brain tissues, cerebrospinal fluid, and diverse AD animal models. Available data consistently support aberrant NLRP3 activation in AD brain, where it is closely associated with amyloid-β (Aβ) deposition, tau pathology, glial reactivity, and cognitive decline. We further discuss the cell-type-specific roles of microglia and astrocytes, highlighting microglia as the principal effector cells in inflammasome-associated pathology. Mechanistically, Aβ and tau converge on NLRP3 activation through interconnected pathways involving K+ efflux, lysosomal rupture, mitochondrial dysfunction, and impaired autophagy. Downstream IL-1β, IL-18, and gasdermin D amplify neuroinflammation and neuronal injury. We summarize emerging therapeutic strategies directly targeting its core components or downstream effectors, as well as anti-AD agents with indirect NLRP3 modulation including endogenous molecules, repurposed drugs, and natural products. Collectively, this review regards NLRP3 inflammasome as a critical inflammatory hub and a promising target for disease-modifying therapy in AD, and provide useful perspectives on AD pathogenesis and inform the development of more rational therapeutic strategies.

The NLRP3 Inflammasome and Pro-Inflammatory Cytokines in Alzheimer's Disease: Molecular Mechanisms, Neuroimmune Crosstalk, Biomarkers, and Emerging Therapeutic Perspectives

The molecular mechanisms underlying NLRP3 inflammasome activation in Alzheimer’s disease, its interaction with pro-inflammatory cytokine networks, and the emerging role of inflammasome-related biomarkers in disease characterization are examined.