Pyroptosis in Alzheimer’s Disease: Mechanisms and Therapeutic Potential

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid plaques, neurofibrillary tangles (NFTs), and neuroinflammation. Recent research has revealed that pyroptosis, an inflammatory programmed cell death (PCD), plays a crucial role in AD pathology. The pyroptosis signaling cascade triggered by β-amyloid (Aβ) and hyperphosphorylated tau protein leads to the release of proinflammatory cytokines, forming a “neuroinflammation-neurodegeneration” vicious cycle. Therapeutic strategies targeting the pyroptosis signaling pathway show promise, with evidence suggesting that inhibition of inflammasomes, caspase-1, or gasdermin D (GSDMD) can alleviate AD-related pathological features. However, the specificity of the existing inhibitors is insufficient, and research on non-classical pyroptosis pathway remains in its early stages. More mechanisms and therapeutic strategies targeting pyroptosis-related pathway need to be explored to enhance the therapeutic efficacy. Targeting the pyroptosis pathway provides a novel direction for AD treatment. Exploring and summarizing its mechanisms along with the clinical translational applications of targeted inhibitors will offer fresh perspectives for moving beyond traditional “symptom control” therapies and achieving “pathology-modifying” interventions, holding significant scientific and clinical importance.

Introduction

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, initially manifests as impairments in language and learning abilities and progresses to cognitive dysfunctions such as behavioral abnormalities and memory loss (Rostagno 2022). AD characterized by an insidious onset and a prolonged course, frequently progressing to severe stages before patients and their families become aware of the symptoms, making its treatment highly challenging (Better 2023). With the accelerating global aging trend, AD and related dementias exert a heavy burden on both individual and society. The pathogenesis of AD remains unknown, with its core pathological hallmarks including abnormal accumulation of β-amyloid (Aβ), tangle of hyperphosphorylated tau protein, and neuroinflammation. Abnormally activated cell death pathways exhibit cumulative effects, driving inflammatory cascades, while neuronal death and brain atrophy represent the terminal outcomes of AD pathology (Huang et al. 2024). Pyroptosis, a newly identified inflammatory form of programmed cell death (PCD), is a key driver of neuronal demise (Moujalled et al. 2021). This progress amplifies inflammation through caspase action, gasdermin D (GSDMD)-dependent signaling, and proinflammatory cytokine release (Pandey et al. 2025). Studies have shown that systemic knockout of inflammasome proteins significantly improves AD pathology in the APP/PS1 model (Heneka et al. 2013), suggesting critical roles for microglia inflammasome activation and neuronal GSDMD cleavage in AD-related neurodegeneration (Moonen et al. 2023). This article reviews recent advances in pyroptosis within AD, highlighting the clinical translational value of targeting pyroptosis inhibitors, thereby providing novel therapeutic targets for AD treatment.

Pyroptosis

The phenomenon of pyroptosis was first described in 1992. Research discovered that infection of mouse macrophages by Shigella flexneri could trigger caspase-1 activation and induce cell death (Yuan et al. 1993). In 2001, studies distinguished this cell death phenomenon induced by Shigella flexneri and Salmonella from apoptosis and formally proposed the term “pyroptosis” (Cookson and Brennan 2001; Boise and Collins 2001). During their investigation of the GSDMD protein, Shao Feng’s team uncovered the underlying mechanism by which caspase activates and recognizes GSDMD in pyroptosis. This discovery revised previous knowledge and indicated that caspase cleaves the GSDMD protein to form membrane pores, which release inflammatory mediators. GSDMD is regarded as the key executor of pyroptosis (Shi et al. 2014; Shi et al. 2015). Pyroptosis is a programmed cell death process that shares features of both necrosis and apoptosis. Pathogen signals stimulate the inflammasome complex, leading to caspase cleavage and activation of the GSDMD signaling pathway, which in turn triggers pyroptosis. Its main characteristics include cell swelling, membrane pore formation, nuclear condensation, and chromatin fragmentation. As cells swell and rupture, their contents (including proinflammatory cytokines) are released, inducing an innate immune response and ultimately resulting in loss of cell membrane integrity (Kovacs and Miao 2017; Imre 2024).

Molecular Mechanism of Pyroptosis

Pyroptosis is classified into classical and non-classical pathways. The classical pathway is triggered by extracellular stimulus signal, which activate innate immunity through pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). These signals recruit apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase-1 to assemble the inflammasome complex, ultimately activating caspase-1. On one hand, this promotes gasdermin (GSDMD) cleavage, releasing the N-terminal fragment, which forms 10–21 nm membrane pores, disrupting the cell osmotic pressure, followed by cell swelling and lysis (Zhang et al. 2018; Fang et al. 2020; Wang and Kanneganti 2021). On the other hand, caspase-1 promotes the maturation and release of IL-18 and IL-1β into the extracellular space, further triggering inflammatory responses (Yu et al. 2021). The non-classical pyroptosis pathway is induced by lipopolysaccharide (LPS), where human caspase-4/5 or murine caspase-11 recognizes and binds to LPS, subsequently cleaving GSDMD to release its N-terminal fragments (GSDMD-NT), which triggers plasma membrane pore formation. Whether caspase-4/5 can directly cleave pro-IL-1β/IL-18 remains controversial, whereas it has been demonstrated that caspase-11 lacks the ability to directly process these pro-forms. In the caspase-11-mediated non-classical pyroptosis pathway, membrane rupture induces K⁺ efflux, which activates the NLRP3 and caspase-1. This cascade ultimately drives the maturation and release of IL-18 and IL-1β (Man et al. 2017; Rao et al. 2022; Rühl and Broz 2015; Aglietti et al. 2016). During pyroptosis, proteins or complexes such as inflammasomes, caspases, and GSDMD play a critical role (Fig. 1).

Fig. 1.

Molecular mechanism of pyroptosis. The classical pathway, activated by PAMPs/DAMPs, assembles ASC and pro-caspase-1 into inflammasomes. Active caspase-1 cleaves GSDMD to form membrane pores and triggers IL-18/IL-1β release. The non-classical pathway involves LPS-induced activation of pro-caspase-4/-5/-11, which cleave GSDMD to generate membrane pores, thereby promoting the release of IL-18 and IL-1β

Inflammasomes

Inflammasomes serve as critical components in innate immunity and are central to the signaling pathways that regulate pyroptosis (Wu et al. 2024). Different inflammasomes vary in their structures, mechanisms of action, and targets. PRRs participate in the formation of inflammasome complexes and are divided into two main groups according to their cellular location: membrane-bound types such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs); and intracellular types including RIG-I-like receptors (RLRs), absent in melanoma 2 (AIM2), and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). When PRRs detect PAMPs or DAMPs, they oligomerize and recruit ASC and pro-caspase-1 to assemble inflammasomes (Kodi et al. 2024; White et al. 2017; Freeman and Ting 2016). Common inflammasomes include AIM2 inflammasome and NLR family inflammasome, with NLRP3 being the most extensively studied (Singh et al. 2023). Mechanistically, PAMP/DAMP stimulation triggers NLRP3 oligomerization, enabling ASC binding and pro-caspase-1 recruitment to form the NLRP3 inflammasome complex. This cascade controls the maturation and secretion of cytokines such as IL-18 and IL-1β, highlighting their essential role in promoting inflammatory disease processes (Dadkhah and Sharifi 2025).

Caspases

In 1993, the caspase protein related to apoptosis was first identified (Yuan et al. 1993), which initiated in-depth research on the caspase protease family. As endopeptidases, caspases act as molecular scissors, regulating biological processes by cleaving substrates. They are categorized into apoptosis-related caspases (e.g., caspase-3, -6 -7), which orchestrate programmed cell death by degrading senescent or damaged cells, and inflammatory-related caspases (e.g., caspase-1, -4 -5, -11), which mediate cytokine-driven inflammatory responses (Ramirez and Salvesen 2018; Svandova et al. 2024; Lu et al. 2020). Emerging studies further link caspases to pyroptosis, with caspase-1 activating proinflammatory cytokines IL-1β and IL-18 post-infection to directly induce lytic cell death (Vande Walle et al. 2016).

Gasdermin D

GSDMD is a member of a protein family with membrane-puncturing ability and highly homologous sequences. In 2015, Shao Feng’ team revealed that caspase-4/11 can directly recognize and cleave GSDMD, thereby triggering pyroptosis. The discovery represented the identification of a further critical substrate of inflammatory caspases following IL-1β and IL-18(Shi et al. 2015). Structurally, GSDMD comprises two functional domains: an N-terminal pore-forming domain (p30 fragment) and a C-terminal autoinhibitory domain (p20 fragment). In its inactive state, the C-terminal domain suppresses the pore-forming activity of the N-terminal domain. Caspase-mediated cleavage releases this autoinhibition, generating two fragments: GSDMD-N (p30) and GSDMD-C (p20). The liberated GSDMD-N domain binds to membrane lipids through its hydrophobic motifs, forming transmembrane pores that disrupt membrane integrity. This permeabilization event triggers osmotic imbalance, culminating in cell rupture and pyroptotic death (Aglietti et al. 2016; Chen et al. 2016; Sborgi et al. 2016; Liu et al. 2016).

Pyroptosis in Alzheimer’s Disease

Neuroinflammation, as a complex and crucial factor in the AD pathological process, is closely associated with the activation of pyroptosis and neuronal death. There is an inseparable connection between pyroptosis and AD, as evidenced by related research reports (Heneka et al. 2013; Anderson et al. 2023; Huang et al. 2022). Moreover, Aβ and hyperphosphorylated tau protein, as the main pathological markers of AD, have also been found to participate in the activation of pyroptosis (Shen et al. 2021; Saresella et al. 2016; Tan et al. 2014). Therefore, exploring the regulatory mechanism of pyroptosis in AD is conducive to clarifying the novel pathological pathways of the disease and also provides an innovative research direction for developing targeted therapeutic strategies.

Neuroinflammation and Pyroptosis

In the central nervous system (CNS), inflammatory responses to injury or infection are typically accompanied by the aggregation of glial cells. NLRP1 is predominantly expressed in neurons, while NLRP3 is mainly localized to microglia (de Rivero Vaccari et al. 2014; Kummer et al. 2007). Notably, elevated inflammasome expression observed in neurons and microglia of AD patients suggests that classical pyroptosis pathways may drive AD-related neuropathological changes (Vontell et al. 2023; Qiu et al. 2023; Cai et al. 2025). NLRP1, the first identified NOD-like receptor, forms a complex with ASC and pro-caspase-1, facilitating caspase-1 activation to promote pyroptosis and downstream inflammation (Zhang et al. 2024a). Postmortem neuropathological analyses of AD patients reveal that NLRP1 expression directly linked to the abundance of NFTs, establishing a connection between neuroinflammation and neurofibrillary pathology (Španić et al. 2022). Tan et al. demonstrated significant upregulation of NLRP1 protein levels in the hippocampal formations of APP/PS1 transgenic mice. Targeted suppression of the NLRP1/caspase-1 axis in AD mice models attenuates neuronal pyroptosis and proinflammatory cytokine release (Tan et al. 2014). Furthermore, suppressing NLRP1 and caspase-1 expression can ameliorate cognitive deficits and exerts neuroprotection (Flores et al. 2022b; Jia et al. 2024; Li et al. 2023b). Mechanistically, chronic glucocorticoid and Aβ stimulation in rat primary neurons exacerbate NLRP1-mediated neuronal damage (Yang et al. 2022). The activation or inhibition of NLRP1 has a crucial impact on cell survival and inflammatory responses, potentially participating in the regulation of AD pathological progression, making it as a potential target for AD therapy.

In APP/PS1 mice with LPS-dependent systemic inflammation, NLRP3 inflammasome activation enhances microglial phagocytic capacity to clear amyloid (Tejera et al. 2019). Furthermore, Aβ deposition is closely associated with the development of inflammasome-dependent ASCs in microglia (Friker et al. 2020). NLRP3 activation induces the production of canonical effector cytokines IL-1β and IL-18. Compared to healthy controls, the levels of proinflammatory cytokines or GSDMD in the cerebrospinal fluid, brain parenchyma, and peripheral blood of AD patients were increased (Shen et al. 2021; McManus 2022; Zhang et al. 2020; Blum-Degen et al. 1995; De Luigi et al. 2001; Torres et al. 2014; Villarreal et al. 2016; Chen et al. 2014), suggesting that NLRP3 might be involved in the pyroptosis process of AD neurons. Under physiological conditions of 4-month-old mice, NLRP3 genetic knockout can lead to impaired synaptic transmission, cognitive impairments, and anxiety-related behaviors (Komleva et al. 2021). In AD mouse models with NLRP3 or caspase-1 knockout, IL-1β secretion decreased, and AD-related symptoms were mitigated (Heneka et al. 2013; Ren et al. 2019). The drug Baicalin (BAI) can suppress NLRP3 activation, thereby mitigating microglial-mediated neuroinflammatory responses (Jin et al. 2019). A pronounced upregulation was observed in both NLRP3 and its downstream effectors IL-18/IL-1β within AD model mice. However, the use of Salidroside (Sal) can suppress the aforementioned phenomenon, thereby inhibiting pyroptosis and relieving neuroinflammation (Cai et al. 2021). These findings indicate that targeting NLRP3 can reduce the release of proinflammatory cytokines, inhibit pyroptosis, and alleviate AD neuropathy (Han et al. 2023). Both upstream inflammasome components and downstream proinflammatory mediators in the pyroptosis pathway are involved in neuroinflammatory responses in AD, and the role of pyroptosis in neuroinflammation cannot be overlooked (Xu et al. 2025).

Aβ and Pyroptosis

The “β-amyloid cascade hypothesis” establishes cerebral amyloid plaque accumulation as a central pathogenic driver in AD, triggering neurotoxic cascades through Aβ oligomerization. These plaques activate microglia, leading to neuroinflammation, synaptic loss, and even neuronal death (Paroni et al. 2019; Webers et al. 2020). Studies have shown that Aβ oligomers/fibrils bind to and activate the NLRP3 inflammasome (Nakanishi et al. 2018), which is essential for Aβ-induced caspase-1 activation and proinflammatory cytokine/chemokine secretion (Halle et al. 2008). Aβ peptide induces pyroptosis of cortical neurons via the NLRP3/caspase-1/GSDMD signaling pathway, resulting in an increase in IL-1β/IL-18. In APP/PS1 mouse models with caspase-1 or GSDMD inhibition, the Aβ-induced pyroptosis phenomenon is attenuated, and proinflammatory cytokines secretion is correspondingly reduced (Han et al. 2020b). Heneka et al. confirmed that Aβ serves as NLRP3 inflammasome primer in microglia and induces cells to transform into an inflammatory M1 phenotype, leading to increased secretion of proinflammatory cytokines and ultimately Aβ deposition and cognitive dysfunction in the hippocampus of mice. Conversely, in APP/PS1/NLRP3^−/− mice, the deficiency of NLRP3 or caspase-1 causes microglia to shift to an M2 phenotype, enhancing Aβ clearance and tissue remodeling. These changes correlate with mitigated spatial memory impairment and dampened neuroinflammation (Heneka et al. 2013).

In APP/PS1 transgenic mice, the expression of NLRP1 is significantly upregulated. In vitro, Aβ can also increase NLRP1 levels in primary cortical neurons, promoting neuronal pyroptosis and proinflammatory cytokines release via the NLRP1/caspase-1 axis. Conversely, genetic ablation of NLRP1 or caspase-1 effectively suppresses neuronal pyroptosis and mitigate cognitive deficits (Tan et al. 2014). The final effector protein of pyroptosis is a member of the gasdermin family. Aβ₄₂-induced pyroptosis depends on the NLRP3/caspase-11/GSDMD/GSDME signaling pathway, where GSDMD knockout inhibits pyroptosis and reduce Aβ deposition (Hong et al. 2023; Jha et al. 2024). Collectively, these findings indicate that Aβ potently induces pyroptosis to exacerbate AD, and molecules related to the pyroptosis pathway may serve as novel therapeutic targets for AD.

Tau and Pyroptosis

Tau is a naturally occurring unfolded microtubule-associated protein that facilitates microtubule assembly and stability. However, hyperphosphorylated tau loses its microtubule-binding capacity, triggering microtubule depolymerization. This leads to subsequent tau misfolding, aggregation into NFTs, and intraneuronal deposition, ultimately resulting in neuroinflammation, neurodegeneration, and cognitive decline (Ossenkoppele et al. 2022; Klyucherev et al. 2022; Monteiro et al. 2023). Blocking NLRP1-dependent pyroptosis reduces the activity of glycogen synthase kinase-3β (GSK-3β) agonists or the effects of streptozotocin (STZ), leading to a decrease in hyperphosphorylated tau (Liu et al. 2022). Panda et al. discovered that fibrillar aggregates of tau-derived PHF6 peptide (VQIVYK) upregulate NLRP3 expression in human microglia and promote the secretion of IL-1β and IL-18 (Panda et al. 2021). Murine models with tau overexpression exhibit NLRP3 activation coupled with upregulated ASC, caspase-1, and IL-1β expression (Zhao et al. 2021). Furthermore, NLRP3 inhibition enhances pericyte viability, improves cerebrovascular function, and ameliorates AD-related pathological changes in tau transgenic murine brain (Quan et al. 2024). The NLRP3 inflammasome can be activated by aggregated tau in primary microglia, accompanied by elevated IL-1β secretion that drives pyroptosis progression. Tau transgenic mice deficient in ASC or NLRP3 exhibited significant reduction in tau pathology and microglial activation (Stancu et al. 2019). These studies suggest that tau might be part of the upstream signal of NLRP3 and participate in the activation of the pyroptosis process. Supporting this paradigm, expressing human frontotemporal dementia (FTD)-mutant tau exhibits NLRP3 hyperactivation and increased ASC speck release. However, NLRP3 suppression diminishes tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. After injecting brain homogenates containing Aβ into the hippocampus of tau22 mice, tau hyperphosphorylated, while tau22 mice with ASC or NLRP3 knockout showed significant improvement (Ising et al. 2019). This study demonstrated that amyloid deposition participates in the tau pathology procession and identifies NLRP3 inflammasome activation as a causal upstream regulator of tau-related neuropathological changes.

The interaction between tau and NLRP3 is complex. On one hand, tau protein aggregates activate NLRP3, promoting ASC formation and inflammatory cytokines expression, and exacerbating neuroinflammation in AD. On the other hand, NLRP3 activation promotes tau hyperphosphorylation and aggregation, thereby accelerating tau pathology progression (Paesmans et al. 2024). Additionally, in mice with simulated tau hyperphosphorylation in the brain, caspase-1 inhibition attenuates tau-induced neuronal damage and rescues cognitive deficits (Li et al. 2020b). Cell-based studies reveal that pyroptosis inhibition mediated by specific blocking agents in neural systems significantly alleviates tau pathology development (Baraka and ElGhotny 2010). Although the association between tau and pyroptosis has been confirmed, the specific mechanism still requires further investigation.

Therapeutic Strategies Targeting Pyroptosis for Alzheimer’s Disease

There is currently no medication that can effectively reverse the progression of AD. Given this, clinical management primarily aimed at delaying disease progression and alleviating symptoms. Targeted therapies, which intervene by addressing specific pathological mechanisms of AD, hold promise for mitigating or even preventing further disease progression. With the expanding understanding of pyroptosis-mediated regulatory networks in AD neuropathology, explorations into drug targets and their applications for pyroptosis-targeted AD treatments have been increasingly reported. Based on the assembly and activity of inflammasomes, the use of specific compounds to block their activation or interact with ASC and pro-caspase opens novel therapeutic avenues for AD intervention. Furthermore, depending on classical or non-classical pyroptosis pathways, targeted inhibition of the activation and secretion of downstream caspase, GSDMD, and inflammatory factors in the inflammasome pathway may also be an effective way to alleviate neuroinflammation in AD. In the following sections, we summarized some inhibitors and their mechanisms of action (Table 1, Fig. 2).

Table 1.

Inhibitors that target pyroptosis for AD

Inhibitor	Class of drug	Mechanism	Significance	References
NLRP3 Inhibitor
Glyburide (GLB)	sulfonylureas	inhibition of ATP-sensitive K+ channels and NLRP3/caspase-1 signaling pathway	reducing Aβ and NFTs deposition, and alleviating neuroinflammation	(Malik et al. 2023; Ju et al. 2020)
JC124	sulfonylureas	inhibition of NACHT domain of NLRP3	reducing Aβ-induced AD pathological phenomenon	(Kuwar et al. 2019; Yin et al. 2018)
MCC950	molecule compound	inhibition of ASC aggregation	alleviating pyroptosis and AD pathological phenomenon	(Dempsey et al. 2017; Li et al. 2020a; Zeng et al. 2021)
OLT1177	β-sulfonyl nitrile compound	inhibition of NLRP3 and ATPase	reducing Aβ deposition and alleviating neuroinflammation	(Marchetti et al. 2018a; Marchetti et al. 2018b; Lonnemann et al. 2020)
Edaravone	substituted 2‐pyrazolin‐5‐ones	inhibition of NLRP3-mediated IL-1β secretion	alleviating Aβ-treated inflammation	(Wang et al. 2017)
CSB6B	pigment	inhibition of NLRP3 and NF-κB signal pathway	inhibiting Aβ aggregation and Aβ-induced cognitive impairments	(Yan et al. 2020)
Oridonin	natural products	inhibition of the cysteine 279 of NLRP3 to block the interaction between NLRP3 and NEK7	attenuating Aβ1–42-induced synaptic loss and cognitive deficits	(Wang et al. 2016; He et al. 2018)
Salidroside	natural products	inhibition of TLR4/NF-κB signaling pathway or TXNIP	depressing Aβ, hyperphosphorylated tau, and alleviating the cognitive disorder	(Cai et al. 2021)
Caspase Inhibitor
VX-765	molecule compound	inhibition of caspase-1	reducing Aβ and NFTs, and alleviating cognitive impairment	(Flores et al. 2018; Flores et al. 2020)
L7	N-salicyloyl tryptamine derivatives	inhibition of NLRP3/caspase-1 signaling pathway	depressing the expression of GSDMD and protecting neuro cell	(Bai et al. 2021)
DJ-1	a gene	inhibition of NLRP3/caspase-1 signaling pathway	depressing the expression of Aβ and alleviating the cognitive disorder	(Liu et al. 2017; Cheng and Zhang 2021)
Z-DEVD-FMK	molecule compound	inhibition of NLRP3/caspase-1 signaling pathway	reducing Alzheimer-like phenotypes	(D’Amelio et al. 2011)
GSDMD Inhibitor
mafenide (MAF)	sulfonamide	inhibition of GSDMD	inhibiting neuroinflammation	(Han et al. 2020c; Han et al. 2021)
Necrosulfonamide (NSA)	molecule compound	inhibition of GSDMD	inhibiting Aβ1‐42‐induced pyroptosis and alleviating behavioral disorder	(Han et al. 2020b; Sun et al. 2012)
Disulfiram (DSF)	tetraethylthiuram disulfide	inhibition of GSDMD	reducing the production of sAPP-α and accumulation of Aβ	(Reinhardt et al. 2018; Libeu et al. 2012; Hu et al. 2020)
miRNA-22	microRNA	inhibition of GSDMD	depressing the expression of Aβ and hyperphosphorylated tau, and alleviating the cognitive disorder	(Han et al. 2020a; Zhai et al. 2021)

Fig. 2.

The mechanism of therapeutic strategies targeting pyroptosis for AD. Glyburide binds to K_ATP channels, MCC950 inhibits ASC oligomerization, OLT1177 suppresses the ATPase activity of NLRP3, CSB6B inhibits the NF-κB signaling pathway, Salidroside inhibits the TLR4/NF-κB pathway or TXNIP expression, and Oridonin binds with the cysteine 279 of NLRP3 in NACHT domain. All these inhibitors ultimately suppress NLRP3 expression or activation. VX-765, Z-DEVD-FMK, DJ-1, and L7 inhibit caspase-1. MAF, NecrosulfonamideDJ-1, Disulfiram, and miRNA-22 inhibit GSDMD cleavage

Therapeutic Strategies Targeting the NLRP3 Inflammasome

Glyburide

Glyburide (GLB), a sulfonylurea compound developed for type 2 diabetes treatment, was primarily characterized by its inhibitory effects on adenosine triphosphatase (ATP)-sensitive K⁺ (K_ATP) channels in pancreatic β-cells (Thévenod et al. 1992; Hardin and Jacobs 2025; Teramoto et al. 2004). Further research has shown that GLB acts upstream of cryopyrin and downstream of the P2X7 receptor, resulting in specific inhibition of NLRP3 activation pathways (Lamkanfi et al. 2009). Sadia et al. used various biophysical techniques, computational methods, and imaging tools to discover that GLB has significant potential in inhibiting amyloid plaque formation (Meeuwsen et al. 2005). In AD rat models, GLB alleviates behavioral abnormalities induced by Aβ and reduces the activity of the HPA axis (Esmaeili et al. 2018). In addition, GLB also inhibits the hyperphosphorylation of tau in the hippocampus of AD mice (Baraka and ElGhotny 2010). Ju et al. reported that GLB reduces Aβ deposition in APP/PS1 mouse hippocampus, suppresses microglial activation, and reduces IL-1β cytokine release (Ju et al. 2020). While these findings highlight GLB’s multifaceted roles, the mechanistic basis of its involvement in AD pathogenesis remains incompletely understood, particularly its effects on neuroinflammation and pyroptosis-related pathways, necessitating further exploration.

JC124

JC124 is a novel small-molecule compound discovered by Marchetti et al., which serves as an intermediate in the synthesis of GLB. This compound selectively inhibits NLRP3 formation and pro-caspase-1 activation, consequently reducing IL-1β production (Marchetti et al. 2015). In a rat model of traumatic brain injury, treatment with JC124 during the acute phase post-injury significantly suppresses injury-induced NLRP3 activation, mitigates neuronal damage, attenuates cerebral inflammatory cell activation, and inhibits the expression of proinflammatory cytokines (Kuwar et al. 2019). For TgCRND8 mice that have clearly shown AD pathological phenomena, JC124 suppresses NLRP3 inflammasome assembly and activation, downregulates Aβ_1-42 expression and amyloid deposition, and also effectively inhibits microglia activation and exert neuroprotective effects (Yin et al. 2018). Research on AD prevention demonstrates that administering JC124 to APP/PS1 mice prior to AD pathology onset inhibits NLRP3, improves cognitive performance, reduces cerebral amyloid deposition, and alleviates cellular inflammatory responses (Kuwar et al. 2021). These findings highlight JC124’s therapeutic potential in AD prevention and treatment through modulation of the NLRP3-pyroptosis pathway, underscoring the need for further in-depth exploration.

MCC950

MCC950 (CRID3) is a small-molecule compound initially identified as a cytokine release inhibitor, which suppresses IL-1β maturation and secretion (Perregaux et al. 2001). Further research shows that MCC950 specifically inhibits ASC oligomerization induced by NLRP3, thereby inhibiting NLRP3 activation and IL-1β secretion (Coll et al. 2015). MCC950 is currently utilized in therapeutic strategies for multiple inflammation-related disorders, including AD (Zeng et al. 2021; Bakhshi and Shamsi 2022). In AD mouse models, MCC950 intervenes in the NLRP3/caspase-1/GSDMD pathway, effectively enhancing spatial memory and reducing amyloid deposits in the mouse brain (Li et al. 2020a). MCC950 blocks NLRP3 activation and IL-1β secretion in microglia, reduces CNS immune activity, enhances microglial clearance of Aβ, and prevents excessive tau phosphorylation in neurons (Li et al. 2023a; Dempsey et al. 2017; Lučiūnaitė et al. 2020). In neonatal rats, MCC950 mitigates ketamine-induced cognitive and behavioral deficits by suppressing the NLRP3/caspase-1 signaling pathway (Zhang et al. 2021). Additionally, MCC950 selectively prevents synaptic dysfunction in a mouse amyloidosis model by targeting NLRP3 inhibition (Qi et al. 2018). These findings collectively suggest that MCC950 holds significant potential in the treatment of AD, although its safety profile and neuroprotective effects require further validation through clinical trials.

OLT1177

The β-sulfonyl nitrile compound OLT1177 specifically targets NLRP3, potently blocking its ATPase activity, thereby blocking the activation of the classical NLRP3 pathway (Marchetti et al. 2018a). OLT1177 is highly specific to NLRP3 and has been applied in the treatment of various diseases, such as cardiovascular diseases and arthritis (Toldo et al. 2019; Marchetti et al. 2018b). Studies in AD mouse models demonstrate that oral administration of OLT1177 significantly reduces microglial activation, inhibits cortical amyloid deposition, and ameliorates cognitive dysfunction. Additionally, it inhibits the inflammatory response triggered by LPS in microglial (Lonnemann et al. 2020). In the microglial of aged rats, OLT1177 suppresses NLRP3 expression and reduces intracellular levels of IL-1β and CD68 (Anton et al. 2024). Currently, a phase 2 clinical trial for OLT1177 in treating gout is actively underway (Klück et al. 2020), and its safety has been demonstrated in phase 1 trials for cardiovascular disease patients (Wohlford et al. 2020). Although research on OLT1177’s role in AD is still limited, its therapeutic potential is noteworthy, warranting further exploration for future clinical applications.

Therapeutic Strategies Targeting Caspase-1

VX-765

VX-765 exhibits high bioavailability, strong blood–brain barrier permeability, and non-toxicity. The oral VX-765 drug for treating epilepsy has entered phase 2 clinical trials (Bialer et al. 2013). In the research on AD, VX-765 has been observed to reverse spatial and episodic memory deficits in J20 mouse models in a dose-dependent manner. Moreover, VX-765 effectively prevents Aβ deposition and reverses neuroinflammatory responses (Flores et al. 2018). In early therapeutic interventions for AD, VX-765 delays the onset of spatial and episodic memory deficits in J20 mouse models during the pre-symptomatic stage. However, while VX-765 mitigates neuroinflammation, it does not significantly affect Aβ levels (Flores et al. 2020). Furthermore, VX-765 alleviates cognitive impairment and tau pathology in mice induced by ketamine, sevoflurane, or propofol by inhibiting the NLRP3/caspase-1 pathway (Zhang et al. 2021; Tian et al. 2021; Zhang et al. 2024b). Focal cortical infarction can lead to Aβ accumulation in the ipsilateral thalamus and further cause secondary damage and inflammatory responses. VX-765 intervention significantly inhibits pyroptosis in the ipsilateral thalamus, reduces proinflammatory cytokines expression, decreases Aβ deposition, and improves post-cerebral infarction cognitive dysfunction (Liang et al. 2025). These results all reveal the important role of VX-765 in modulating pyroptosis and combating AD pathology. Nevertheless, controversies persist regarding its effects on amyloid deposition and neuroinflammation. Flores et al. noted that while caspase-1 inhibition improves spatial and episodic memory deficits in AD mice, it does not significantly ameliorate amyloid deposition or inflammation levels (Flores et al. 2022a). Based on current evidence, VX-765 may alleviate cognitive impairment and AD pathology by inhibiting pyroptosis. Moreover, as a relatively safe drug, VX-765 may have potential application value in the prevention and treatment of AD.

Therapeutic Strategies Targeting GSDMD

Sulfonamide Drugs

Mafenide (MAF), a sulfonamide antibiotic, exhibits broad-spectrum efficacy against both Gram-positive and Gram-negative bacterial strains (Fernández et al. 1992). In microglia undergoing LPS-induced pyroptosis, MAF blocks GSDMD cleavage by directly targeting the GSDMD-asp275 site, lowers p30-GSDMD levels, and decreases proinflammatory cytokine release. MAF also reduces proinflammatory cytokine levels in the cerebrospinal fluid and peripheral blood of APP/PS1 mice and inhibits microglial activation (Han et al. 2020c). MAF derivatives Sulfa-4 and Sulfa-22 exhibit superior efficacy compared to MAF, significantly inhibiting p30-GSDMD production, NLRP3 and caspase-1 expression, and reducing microglial activation and proinflammatory cytokines expression (Han et al. 2021). Although research on MAF in neurodegenerative diseases is limited, its potential therapeutic value in AD treatment cannot be overlooked, warranting further investigation.

microRNA-22

MicroRNAs (miRNAs) are endogenous non-coding single-stranded RNA molecules approximately 18–25 nucleotides in length, which participate in diverse biological processes through the regulation of gene expression. MiRNAs directly target specific genes to modulate molecular expression. Han et al. demonstrated that AD patients show decreased peripheral blood miRNA-22 expression compared to healthy controls, and proinflammatory cytokines expression are negatively correlated with miRNA-22. Subsequent research demonstrated that miRNA-22 modulates neuroglial pyroptosis by directly suppressing GSDMD expression, which reduces proinflammatory cytokine secretion and alleviates cognitive deficits in AD murine models (Han et al. 2020a). Exosomes containing miRNA-22 (Exo-miRNA-22) secreted by adipose-derived mesenchymal stem cells (ADMSC) were shown to effectively suppress GSDMD and p30-GSDMD expression, reduce NLRP3/caspase-1/GSDMD pathway components, and attenuate microglial pyroptosis along with cognitive and memory deficits in AD mouse models (Zhai et al. 2021). The targeted treatment of miRNA is closely related to neuroprotection and anti-neuroinflammation, and the discovery of miRNA-22 offers a novel potential approach for AD treatment, deserving further in-depth research.

Translational Relevance of Targeting Pyroptosis in Alzheimer’s Disease

Research on the mechanisms of pyroptosis has revealed its central role in AD. The activation and interaction of Aβ and tau pathology with pyroptosis pathways provide novel insights for AD treatment, making the identification of pyroptosis-targeted strategies and their clinical translation critically important. Small-molecule inhibitors, owing to their ease of administration, low production costs, and high optimization potential, have become a core focus in drug development. NLRP3 inhibitors such as MCC950 have demonstrated therapeutic efficacy in various preclinical models, including atherosclerosis (Zeng et al. 2021), diabetes (Yin et al. 2018), steatohepatitis (Mridha et al. 2017), and AD (Dempsey et al. 2017). Although MCC950 effectively inhibits the NLRP3-pyroptosis pathway, its Phase II clinical trial for rheumatoid arthritis was suspended due to hepatotoxicity (Mangan et al. 2018). OLT1177, currently in clinical trials for gout and cardiovascular diseases, exhibits significant potential in suppressing pyroptosis and alleviating AD pathology. Its specific inhibition of NLRP3 reduces off-target risks, enabling progression to preclinical studies. GLB, used in type 2 diabetes, targets the NLRP3 inflammasome in vitro to improve AD pathology (Malik et al. 2023), but its clinical translation remains challenging due to high-dose requirements in vivo and unclear mechanisms. Additionally, Telmisartan, an FDA-approved anti-hypertensive drug, mitigates AD neuroinflammation by inhibiting the microglial PPARγ/NLRP3 pathway (Fu et al. 2023), but its clinical value still needs to be further studied.

The oral drug VX-765, in Phase II trials for epilepsy (Bialer et al. 2013), shows neuroprotective effects in AD animal models by blocking caspase-1-mediated pyroptosis pathway. However, symptom recurrence upon withdrawal necessitates long-term administration, and its hepatotoxicity complicates clinical application (MacKenzie et al. 2010). While miRNA therapies have not yet entered AD clinical trials, intranasal delivery of miR-146a agomir rescues pathological and cognitive deficits in AD mouse models, providing a novel translational avenue. Despite the clear preclinical efficacy of pyroptosis-targeting compounds, their clinical translation faces challenges such as sustained efficacy, safety validation, and patient stratification (Mai et al. 2019). Future efforts require integrating precision medicine strategies and multidisciplinary collaboration to advance these therapies for AD treatment, offering new interventions for neurodegenerative diseases.

Discussion and Conclusion

This review systematically elaborates on the mechanisms of pyroptosis in the pathogenesis of AD and targeted therapeutic strategies against pyroptosis. It highlights the clinical translational value of molecular agents in AD treatment, offering novel therapeutic targets and pathology-modifying strategies for AD therapy. During the pathological process of AD, the persistent activation of neuroinflammation is closely related to pyroptosis, and the abnormal aggregation of Aβ and tau can directly trigger the pyroptosis signaling pathway by activating inflammasomes (such as NLRP3), forming a vicious cycle of “inflammation-neurodegeneration.” By inhibiting pyroptosis and the subsequent inflammatory responses, it is expected to prevent and alleviate the pathological phenomena related to AD. In the pathological progression of AD, multiple pyroptosis pathways may be concurrently activated. A systematic investigation and synthesis of the mechanisms and effects of pyroptosis pathways in AD could help elucidate the complex impacts of their crosstalk, thereby highlighting the critical need for this comprehensive review.

During the drug development process, some researchers focused on targeting downstream proinflammatory cytokines such as IL-1β of pyroptosis (Dubois et al. 2011; Kitazawa et al. 2011; Batista et al. 2021; Klein et al. 2020; Ridker et al. 2017). With the progressive elucidation of pyroptotic mechanisms, therapeutic approaches suppressing cytokine production at the source through upstream pathway modulation demonstrate improved therapeutic precision. However, interventions targeting the NLRP3/caspase-1/GSDMD axis may still incur off-target effects, highlighting the need for advanced molecular engineering to optimize pyroptosis inhibitor specificity. Notably, studies on targeting non-classical pyroptosis pathway are still in its infancy. Mohamed found that Palonosetron/methyllycaconitine inhibits the progression of sporadic AD by downregulating ASC expression and suppressing the activation of caspase-11 and caspase-1 (Mohamed et al. 2021). However, in Han’s study, Aβ_1-42 induces upregulation of p30-GSDMD and caspase-1 levels in mouse neurons, but exhibits no significant effect on caspase-11 expression (Han et al. 2020b). These controversies underscore the necessity for parallel in-depth investigations into non-classical pyroptosis pathways to identify novel therapeutic targets. In addition, pyroptosis may have cross-regulation with the pathological mechanism of AD, which suggests the feasibility of combination therapies. For instance, synergistic strategies combining pyroptosis inhibitors with anti-Aβ biologics like lecanemab warrant exploration for enhanced therapeutic efficacy (Vitek et al. 2023; van Dyck et al. 2023). In summary, pyroptosis not only acts as a core driver of AD pathogenesis but also offers a novel perspective for moving beyond traditional “symptom control” approaches toward achieving “pathological modification.” Targeting pyroptosis as an emerging therapeutic strategy holds promise for unraveling the mysteries of AD pathogenesis and delivering more effective treatments for patients.

Author Contribution

Only T wrote and reviewed this manuscript.

Funding

There is no funding.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

The manuscript does not contain clinical studies or patient data.