Targeting the NLRP3 inflammasome pathway associated with neuroinflammation mediated Alzheimer's disease: pre-clinical and clinical status of emerging therapeutics.
Aug 2026· Expert opinion on therapeutic targets· pp. 1-20· 0 citations· 129 references
Medicine
TL;DR
This review breaks down the pathways triggered by immune cells activation (neurotoxic microglial phenotype) and majorly focusing over the NLRP3 inflammasome neuroinflammation pathway, exploring the promising therapeutic potential of specific bioactive phytochemicals, repurposed and novel synthetic drugs/agents to shut-down this molecular switch.
Abstract
INTRODUCTION
Alzheimer's disease (AD) is a rising global health problem, but current treatments only target symptoms rather than fixing their underlying root causes. A major pathological feature is neuroinflammation, which is specifically driven by the Nucleotide-binding domain, Leucine-rich-repeat and Pyrin domain-containing 3 (NLRP3) inflammasome cascade, which acts as a 'molecular switch' that causes immune cells in the brain to trigger robust secretion of pro-inflammatory cytokines (e.g. IL-1β, IL-18) and pyroptosis, causing systemic inflammation, thereby the neuroinflammation.
AREAS COVERED
This review breaks down the pathways triggered by immune cells activation (neurotoxic microglial phenotype) and majorly focusing over the NLRP3 inflammasome neuroinflammation pathway. It explores the promising therapeutic potential of specific bioactive phytochemicals, repurposed and novel synthetic drugs/agents, to shut-down this molecular switch i.e. NLRP3 inflammasome pathway.
EXPERT OPINION
To truly stop AD, we must shift our focus from treating merely the symptoms, by stopping the disease at its roots. While discovering the novel NLRP3 inflammasome inhibitors is exciting, but the biggest hurdle is getting them into the brain. Future of AD treatment relies on combining these targeted drugs with advanced nanotechnology, like nano-particles, to successfully cross the blood-brain barrier (BBB) and safely deliver the drugs exactly where they are needed.
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.
Hira Shabbir· Scholars International Journ...· 0 citations
This review regards NLRP3 inflammasome as a critical inflammatory hub and a promising target for disease-modifying therapy in AD, and provides useful perspectives on AD pathogenesis to inform the development of more rational therapeutic strategies.
Wenwen Lian, Fulin Zhou, Zhuohang Tong et al.· Ageing Research Reviews· 0 citations
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.
Almas Meheboob Pathan· International Journal of The...· 0 citations
The gut–brain axis has evolved into a bidirectional neuroimmune communication network linking microbial ecology, innate immunity, endocrine signaling, and central nervous system function. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a key cytosolic sensor that converts signals from microbes into pro-inflammatory pathways. Growing evidence shows that changes in microbial metabolites, intestinal permeability, and systemic immune activation caused by dysbiosis all lead to NLRP3 inflammasome signaling in microglia, astrocytes, and neurons. This neuroinflammatory response mediated by the inflammasome has been progressively associated with the pathophysiology of autism spectrum disorder (ASD) and stress-related neuropsychiatric diseases, such as anxiety and post-traumatic stress disorder. Gut microbial disturbances facilitate peripheral cytokine release, compromise the blood–brain barrier, induce mitochondrial stress, and generate reactive oxygen species—all of which are crucial upstream activators of NLRP3. The development of interleukin (IL)-1β and IL-18, which depends on inflammasomes, worsens synaptic plasticity, neurotransmitter balance, and control of the hypothalamic–pituitary–adrenal axis. In this review, we integrate novel mechanistic findings that link gut microbiota dysregulation to NLRP3-mediated neuroinflammation, clarify its involvement in ASD and stress susceptibility, and examine treatment approaches targeting microbial modulation and inflammasome suppression. Comprehending this immunometabolic axis may facilitate targeted neuroimmune therapies for neurodevelopmental and stress-related diseases.
Alzheimer’s disease (AD) is now widely accepted as a complex disorder involving multiple interconnected pathological processes. Increasing evidence suggest that neuroinflammation and immune system dysregulation actively contribute to neurodegeneration, extending beyond the traditional view that the disease is driven solely by amyloid-β (Aβ) and tau pathology. With the advent of studies showing anti-amyloid antibodies to have only modest effects with significant toxicity, there has been a growing interest in investigating non-amyloid non-tau (NANT) treatment approaches. This review provided a general review of small molecules for neuroinflammation-based NANT therapies in AD. We reviewed several agents that affect the brain/immune axis, namely, kinase inhibitors (nelflamaimod and masitinib), NLRP3 inflammasome inhibitors (MCC950, selnoflast, and dapansutrile), TREM2 activators (VG-3927), gingipain inhibitors, PPARγ activators, KCa3.1 inhibitors, and repurposed drugs such as ambroxol and cromolyn. Some common drawbacks were identified for the drugs that failed to provide their anticipated effects. It was found that they all suffered from late-stage treatment, patient heterogeneity, inadequate central nervous system penetration, and poorly designed preclinical studies. Additional translational challenges included sex-specific differences in neuroimmune responses, APOE ε4-associated immune dysfunction, and the need for biomarker-guided patient selection. Although immune-targeted therapies remain strongly supported by biological evidence in AD, meaningful clinical progress will likely require earlier intervention strategies guided by biomarkers and therapies capable of targeting multiple disease pathways simultaneously.
Niti Sharma, Seong Soo A. An· Molecules· 0 citations
Background: Multiple sclerosis (MS) is a chronic neurodegenerative and demyelinating disease that is marked by chronic inflammation of the central nervous system (CNS). Although interferon-β (IFN-β) remains one of the pillars of treatment for relapsing-remitting MS (RRMS), inconsistencies in the responses of patients signify the necessity to comprehend the immunopathological processes.Objectives: The NLRP3 (NOD-like receptor family pyrin domain-containing 3) inflammasome, an intracellular signaling platform controlling the activation of caspase-1 and the maturation of interleukin-1β (IL-1β) and interleukin-18 (IL-18) has been of considerable interest among emerging molecular actors. Microglia, the native CNS macrophage, are the center stage of tissue damage and repair.Results: Demyelination and axonal degeneration in neuroinflammation are linked to the role of aberrant activity of the microglial NLRP3 inflammasome. In addition, it is also suggested that an inhibition of inflammasome by IFN-β can be observed in a mechanistic interaction between NLRP3 signaling and response to treatment.Conclusion: In this literature review, the presented data summarize the existing information about the contribution of NLRP3 to the pathogenesis of MS disease, microglial activation, and IFN-β regulation, and how this pathway can be applied to shape personalized treatment approaches.
Prathyusha Koyya, Hemasundar Alavilli, S. Pandrangi et al.· Immunological Investigations· 0 citations
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