Alzheimer’s disease (AD) is a common progressive neurodegenerative disease characterized by central nervous cell dysfunction and neuronal loss (Masters et al., 2015; DeTure and Dickson, 2019). The main pathological hallmarks of AD are amyloid plaque and neurofibrillary tangles (NFTS), which are usually interpreted as amyloid-β (Aβ) aggregates and highly phosphorylated tau protein deposits, respectively (Price et al., 2014; Fricker et al., 2018). In the amyloid cascade hypothesis proposed by Hardy in 1991, the sequence of pathological changes in AD is from Aβ deposition to tau aggregation and subsequent neuronal damage, emphasizing the role of Aβ and tau deposition in the progression of AD (Hardy and Allsop, 1991). However, the current study suggests that neuroinflammation and pyroptosis are also key for pathological changes in AD (De Strooper and Karran, 2016; Stephenson et al., 2018). Neuroinflammation is thought to be responsible for a variety of CNS diseases, including AD, Parkinson’s disease (PD), Multiple Sclerosis (MS), etc. (Zhang et al., 2017; Heneka et al., 2018; Feng et al., 2020). Elevated levels of inflammatory factors such as IL-1β and IL-18 are often found in central system lesions, and upregulation of these cytokines implies possible neuronal damage or death, as they trigger a severe inflammatory cascade (Allan et al., 2005; Alboni et al., 2010; Spulber and Schultzberg, 2010). The increase in the levels of these factors means that neurons may be damaged or die because they trigger a series of severe inflammatory cascades.

In the current study, aggregated Aβ and tau activation of NLRP3 (NOD-like receptor protein 3) inflammasome-mediated neuroinflammatory responses and neuronal pyroptosis were found in AD patients and animal models, whereas inhibition of this set of responses attenuated the progression of AD (Meda et al., 1995; Tan et al., 2014; Han et al., 2020b; Perea et al., 2020). This suggests that neuroinflammation and pyroptosis may be potential targets in the direction of AD therapy. While the role of neuroinflammation in the course of AD is well-established, the mechanism and mode of action of pyroptosis in AD has not been systematically elucidated (Yap et al., 2019; Onyango et al., 2021). This article systematically reviews the role of CNS cellular pyroptosis in the progression of neurodegenerative diseases, especially AD, including the cell types and mediators involved, as well as potential targeted therapeutic approaches.

Pyroptosis, a term coined by Cookson and Brannan, is a new form of programmed cell death that exhibits typical features of apoptosis and necrosis. Similar to apoptosis, cellular pyroptosis causes DNA damage and is TUNEL-positive. As with necrosis, cells form transmembrane pores under septic action, releasing proinflammatory cytoplasmic contents that can eventually induce cell rupture (Xie et al., 2020). The body can use a number of mechanisms to sense intra- and extracellular “danger” signals generated by invading pathogenic microbes or tissue damage. Activated Toll-like receptors (TLRs) initiate a signaling cascade that leads to cellular activation and production of inflammatory cytokines such as tumor necrosis factor (TNF), IL-6, IL-8 and type I interferons (IFNs) (Kawai and Akira, 2007). The role of Nod like receptors (NLRs) is to recognize danger signals introduced into the host cell and some NLR proteins, such as NLR family CARD domain-containing protein (NLRP)1/3, NLRP1b, NLRC4, NAIP5, NLRP6/9 are present in the same complex and play a role in sensing bacterial toxins and secretions, nucleic acids, pathogenic crystals and denatured cellular components, and synergistically activate caspase 1, ultimately leading to cellular pyroptosis and release of the inflammatory cytokines IL-18 and IL-1β (Fink et al., 2008; Bergsbaken et al., 2009; Levy et al., 2015; Zhu et al., 2017; Liu et al., 2018). In this process, many inflammasomes form an inflammasomes complex by recruiting apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and promoting ASC polymerization into large filamentous to activate caspase-1, while some inflammasomes (e.g., NLRP1 and NLRC4) can bind directly to caspase-1 (Kesavardhana et al., 2020). Although pyroptosis has been thought to be a caspase-1-driven monocyte death pathway (canonical pathway), caspase-4, –5 and –11 were later found to effectively drive pyroptosis as well (non-canonical pathway). Inflammatory caspase-4, –5, and –11 act as direct receptors that sense pathogen-encoded molecules, such as lipopolysaccharide (LPS), and undergo self-oligomerization and proximally induced self-activation (Zanoni et al., 2016; Chu et al., 2018).

There are six known members of the GSDM family including GSDM-A, -B, -C -D, -E (also known as DFNB5) and DFNB59. Structurally, all GSDM members except DFNB59 have an N-terminal pore-forming structural domain, a C-terminal self-inhibitory structural domain and a loop structural domain connecting the N-terminal and C-terminal. Protease-mediated cleavage within the junctional loop can lead to the release of the GSDM N-terminal, which then forms non-selective pore channels in the plasma membrane through its oligomerization and leads to membrane rupture and subsequent pyroptosis (Zhang J. Y. et al., 2021). In 2015, gasdermin (GSDM) D was identified as a key mediator of caspase-1, –4, –5, and –11-induced pyroptosis, and these caspases activate GSDMD through protein hydrolysis, leading to pore formation and cell pyroptosis at the plasma membrane (Kayagaki et al., 2015; Shi et al., 2015). Metabolite α-ketoglutarate (α-KG) induces pyroptosis through caspase-8-mediated cleavage of Gasdermin C (GSDMC) (Zhang J. Y. et al., 2021). In addition, Caspase-8 can also mediate GSDMD cleavage and thus induce pyroptosis (Xia, 2020). Recent research have reported that streptococcus induces pyroptosis through directly shear GSDMA (Zhao et al., 2022). In addition to GSDMA, GSDMC and GSDMD, the upstream regulatory mechanisms of GSDMB, GSDME and DFNB59 still need to be further explored. The GSDMD consists of an N-terminal pore-forming structural domain, a C-terminal regulatory structural domain and a central junctional region (Ding et al., 2016; Liu et al., 2016). The GSDMD-N-terminal fragments bind to phospholipids such as phosphatidylinositol phosphate, phosphatidic acid, phosphatidylserine and cardiolipin in the inner leaflet of the plasma membrane. Then, the GSDMD-N-terminal fragments undergo sequential conformational changes, which promote their aggregation and membrane insertion, culminating in the formation of membrane pores with an inner diameter of 10–15 nm (Ruan et al., 2018; Liu et al., 2019). The formation of plasma membrane pores promotes the loss of concentration gradients, cell swelling, and ultimately cell lysis and the release of pro-inflammatory molecules and organelles such as nucleotides, IL-1 family cytokines, HMGB1, nucleic acids, mitochondria, etc. (Tsuchiya, 2021). In addition, caspase-3 proteolysis via Gasdermin E (GSDME) can convert tumor necrosis factor (TNF) or chemotherapy-induced apoptosis into pyroptosis (Monack et al., 1996). Adenosine triphosphate (ATP) is released into the extracellular space after cell injury and activates P2 × 7 receptor (P2 × 7R), an ATP-gated potassium channel that promotes potassium efflux while promoting calcium inward flow, which ultimately activates inflammasome-induced pyroptosis by activating Calmodulin kinases II (CAMKII) (Ratsimandresy et al., 2013; Kesavardhana et al., 2020). These will further promote the onset of cellular pyroptosis (Figure 1).

This paper focuses on elucidating the mechanisms of pyroptosis-mediated AD pathogenesis and the progress of experimental studies on regulating pyroptosis in AD therapy. It is well-known that inflammasome NLRP1, NLRP3, NLRP4, and AIM2 can initiate pyroptosis-related downstream signals under the stimulation of various external factors. A large number of studies have now shown that the AD-associated pathological marker Aβ can induce pyroptosis-related neuronal damage by activating NLRP1 and NLRP3, which leads to AD progression. Therefore, neuronal pyroptosis may become an important pathogenic mechanism and marker of AD progression. However, the relationship between p-tau and neuronal pyroptosis are still barely reported and the specific molecular mechanisms still need to be further explored. In addition to the role of NLRP1 and NLRP3 in neuronal pyroptosis elucidated in AD models, the potential link between other pyroptosis-related inflammasomes and pathological markers of AD also deserves further research exploration. Furthermore, in addition to neurons in cortical, hippocampal and other brain regions mentioned above, abnormalities in glial cells such as microglia and astrocytes all play a key role in the pathogenesis and progression of AD (Bartels et al., 2020). Interestingly, recent studies have shown that ASC released by microglia pyroptosis binds to Aβ in the intercellular fluid to form ASC-Aβ polymers, thereby preventing phagocytic degradation of Aβ and promoting pyroptosis of neighboring cells (Venegas et al., 2017; Heneka et al., 2018; Lučiūnaitė et al., 2020). Thus, pro-inflammatory polarization and pyroptosis-induced neuroinflammation in microglia mediates Aβ-induced sustained injury. This evidence suggests a pathogenic role for non-neuronal glial cell pyroptosis in AD. More studies between pyroptosis and AD pathogenesis in the glial cell context need to be further developed. In addition to central nervous system inflammation, the extrinsic relationship between systemic inflammation and AD has been revealed by recent studies. These studies have demonstrated the potential of pyroptosis pathway-related proteins in peripheral blood mononuclear cells as markers of AD. However, the specificity of this peripheral marker remains to be evaluated given the broad association between pyroptosis and multiple neurological disorders.

Of interest is the remarkable progress in drug research targeting the Aβ/tau-induced pyroptosis-related pathway. Different drugs can not only attenuate neuronal loss by targeting cortical and hippocampal neurons, but also protect the blood-brain barrier by inhibiting glial cell and vascular endothelial cell pyroptosis, thereby inhibiting pathological Aβ aggregation in the brain interstitial fluid. As an intervention tool, a large number of non-coding RNAs show greater potential for the targeted modulation of focal death pathway proteins. However, a large number of drug studies are still limited to targeting NLRP3 or NLRP1/caspase-1/GSDMD classical pyroptosis pathway to inhibit neuronal pyroptosis in AD-related regions and thus alleviate AD symptoms. A more in-depth study of the link between pyroptosis and AD pathogenesis would be beneficial for drug development. In addition, it is promising that human clinical studies have found increased levels of pyroptosis-related proteins in the cerebrospinal fluid of AD patients and that pyroptosis regulatory targets related to AD pathogenesis have been identified in human neuronal cells. In conclusion, this study summarizes most of the current clues linking the relationship between AD and pyroptosis, and this evidence suggests that pyroptosis holds great promise and feasibility for the study of AD pathogenesis and drug development, and targeting pyroptosis will provide new opportunities for the treatment of AD.

TW designed this article. YH, XL, and GL wrote the manuscript. JW and RL prepared figures. TW and FY critically revised the manuscript for important intellectual content. All authors have read and approved the final manuscript and agreed to be accountable for all aspects of this work.