Jul 2026· Journal of Dynamics and Control· Vol 10, pp. 351-390· 0 citations
TL;DR
The present review aims to delve into the potential mechanism of action of Dalbergia sissoo in Alzheimer’s disease, focusing on the interaction between the P2X7 receptor and NLRP3 inflammasome.
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder presenting memory loss, cognitive decline, synaptic dysfunction and irreparable neuronal damage. It is the most common dementia disorder in the world, and a major public health problem. Although much research has been done into this, no pharmacologic treatments yet exist that can effectively prevent or reverse disease progression and only offer symptomatic relief. The purinergic P2X7 receptor and the subsequent NLRP3 inflammasome signaling pathway have well established as key players in the regulation of neuro-inflammatory responses in AD. Extracellular ATP binding to the P2X7 receptor leads to assembly of the NLRP3 inflammasome complex. Caspase-1 activation and further increase in the production of pro-inflammatory cytokines like interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), speed up the injury of neurons and disease progression. As a natural alternative remedy, medicinal plants with multi-target pharmacological activities have been an object of special interest for the treatment of AD. Dalbergia sissoo Roxb. Sheesham is a common medicinal tree of the Fabaceae family that has been traditionally utilized for inflammatory, neurological and oxidative stress disorders. Plant have shown the presence of various bioactive compounds such as flavonoids and phenolic compounds, with notable antioxidant, anti-inflammatory and neuroprotective effects. The therapeutic properties of Dalbergia sissoo can be linked to its anti-oxidative properties, down-regulation of pro-inflammatory cytokines and protection of neuronal cells from inflammatory damage. Recently increases of its phytochemical ingredients may affect ATP-mediated activation of P2X7 receptor and inhibition of NLRP3 inflammasome signalling in Alzheimer’s disease. The present review aims to delve into the potential mechanism of action of Dalbergia sissoo in Alzheimer’s disease (AD), focusing on the interaction between the P2X7 receptor and NLRP3 inflammasome.
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
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.
Wenwen Lian, Fulin Zhou, Zhuohang Tong et al.· Ageing Research Reviews· 0 citations
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.
Devesh Yaduvanshi, Rishabh Aggarwal, Sameeya A et al.· Expert opinion on therapeuti...· 0 citations
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
Alzheimer's disease (AD) is the most common neurodegenerative disorder and is characterized by progressive cognitive decline, cholinergic dysfunction, oxidative stress, and neuroinflammation. Despite extensive research, effective disease-modifying therapies remain unavailable. 6-Hydroxyflavanone (6-OH-F), a naturally occurring flavonoid with antioxidant and anti-inflammatory properties, has not been investigated in AD. This study evaluated the neuroprotective potential of 6-OH-F against amyloid-β (Aβ)-induced AD pathology. Network pharmacology was employed to identify potential targets and pathways associated with 6-OH-F in AD. Neuro-2a cells were pretreated with 6-OH-F (12.5-50 μM) before Aβ exposure, followed by assessment of cell viability, reactive oxygen species (ROS), acetylcholinesterase (AChE), NLRP3, TNF-α, and IL-1β levels. AD was induced in mice by intracerebroventricular administration of pre-aggregated Aβ. Animals received 6-OH-F (15, 30, or 60 mg/kg, p.o.) for four weeks. Behavioral, biochemical, molecular, imaging, and histopathological analyses were subsequently performed. Network pharmacology revealed significant overlap between 6-OH-F targets and AD-associated genes, with enrichment of pathways related to neuronal function and inflammation. In vitro, 6-OH-F attenuated Aβ-induced cytotoxicity and reduced ROS, AChE, NLRP3, TNF-α, and IL-1β levels. In vivo, 6-OH-F improved cognitive performance, alleviated oxidative stress and cholinergic dysfunction, and suppressed the expression of TLR4, pNF-κB, NLRP3, ASC, caspase-1, GSDMD, pro-inflammatory cytokines, IBA1, and GFAP. Furthermore, it reduced neuronal degeneration, blood-brain barrier disruption, and cerebral hemodynamic abnormalities. 6-OH-F ameliorates Aβ-induced cognitive impairment by attenuating oxidative stress, neuroinflammation, and pyroptotic signaling, potentially through modulation of the TLR4/NF-κB/NLRP3 pathway, highlighting its therapeutic potential in Alzheimer's disease.
As life expectancy increases worldwide, the proportion of people aged 65 and older is expected to double by 2050 and these global demographic shifts will be accompanied by an increase in age-related neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s disease (PD). AD is the leading cause of dementia worldwide, characterized by progressive cognitive decline linked to amyloid beta accumulation, tau pathology, neuronal cell death and chronic neuroinflammation. PD is the most common movement disorder worldwide, characterized by progressive motor decline linked to alpha-synuclein accumulation, formation of Lewy bodies and neurites, dopaminergic neuron death, as well as chronic neuroinflammation. Increasing evidence implicates inflammasomes, intracellular multiprotein complexes that orchestrate innate immune responses, as key drivers of the neuroinflammatory milieu in AD and PD. The NLRP3 inflammasome, mostly expressed by microglia, has been shown to activate caspase-1, resulting in the cleavage and release of pro-inflammatory cytokines IL-1β and IL-18 and promoting pyroptotic cell death within the central nervous system. This review synthesizes current knowledge on the molecular mechanisms of inflammasome activation, their pathological involvement in AD and PD, and the genetic underpinnings supporting their role. It further highlights emerging therapeutic strategies aimed at modulating inflammasome activity, evaluating preclinical outcomes and clinical trial progress. Understanding inflammasome dynamics provides critical insight into AD and PD pathophysiology and presents promising targets for future disease-modifying treatments.
C. Tropis, Janna Jernigan Posey, M. Tansey et al.· Molecular Neurodegeneration· 0 citations
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