Pyroptosis executive protein GSDMD as a biomarker for diagnosis and identification of Alzheimer’s disease

Shen, Heping; Han, Chenyang; Yang, Yi; Li, Guo; Sheng, Yongjia; Wang, Jin; Li, Wenyan; Zhai, Liping; Wang, Genghuan; Guan, Qing

doi:10.1002/brb3.2063

Cited by 42 publications

(33 citation statements)

References 26 publications

(22 reference statements)

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“…While there is some indirect evidence implicating tau and activation of regulated forms of necrosis like pyroptosis [ 32 ], parthanatos [ 33 ] and ferroptosis [ 34 , 35 ], reviewed in [ 5 ], necroptosis has been more directly implicated in AD. Initial studies were based on the elevated expression of RIPK1 that correlated with Braak staging [ 36 ].…”

Section: Tau Aggregation or Pathology And Regulated Types Of Necrosis – Focus On Necroptosismentioning

confidence: 99%

Tau aggregation and its relation to selected forms of neuronal cell death

Tolkovsky

Spillantini

2021

Essays in Biochemistry

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How neurons die in neurodegenerative diseases is still unknown. The distinction between apoptosis as a genetically controlled mechanism, and necrosis, which was viewed as an unregulated process, has blurred with the ever-increasing number of necrotic-like death subroutines underpinned by genetically defined pathways. It is therefore pertinent to ask whether any of them apply to neuronal cell death in tauopathies. Although Alzheimer’s disease (AD) is the most prevalent tauopathy, tauopathies comprise an array of over 30 diseases in which the cytoplasmic protein tau aggregates in neurons, and also, in some diseases, in glia. Animal models have sought to distil the contribution of tau aggregation to the cell death process but despite intensive research, no one mechanism of cell death has been unequivocally defined. The process of tau aggregation, and the fibrillar structures that form, touch on so many cellular functions that there is unlikely to be a simple linear pathway of death; as one is blocked another is likely to take the lead. It is timely to ask how far we have advanced into defining whether any of the molecular players in the new death subroutines participate in the death process. Here we briefly review the currently known cell death routines and explore what is known about their participation in tau aggregation-related cell death. We highlight the involvement of cell autonomous and the more recent non-cell autonomous pathways that may enhance tau-aggregate toxicity, and discuss recent findings that implicate microglial phagocytosis of live neurons with tau aggregates as a mechanism of death.

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Section: Tau Aggregation or Pathology And Regulated Types Of Necrosis – Focus On Necroptosismentioning

confidence: 99%

Tau aggregation and its relation to selected forms of neuronal cell death

Tolkovsky

Spillantini

2021

Essays in Biochemistry

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“…Therefore, death neuronal is a root reason for AD and other neurodegenerative diseases (Hambright et al, 2017). Furthermore, emerging evidence indicates pyroptosis may serve as the predominant form of neuronal death in AD following apoptosis, autophagy, and necrosis (Fricker et al, 2018;Shen et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Salidroside Ameliorates Alzheimer's Disease by Targeting NLRP3 Inflammasome-Mediated Pyroptosis

Cai

Chai

et al. 2022

Front. Aging Neurosci.

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Amyloid β-protein (Aβ) is reported to activate NLRP3 inflammasomes and drive pyroptosis, which is subsequently involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). To date, the pathogenesis of AD is unfortunately insufficiently elucidated. Therefore, this study was conducted to explore whether Salidroside (Sal) treatment could benefit AD by improving pyroptosis. Firstly, two animal models of AD, induced, respectively, by Aβ1-42 and D-galactose (D-gal)/AlCl3, have been created to assist our appreciation of AD pathophysiology. We then confirmed that pyroptosis is related to the pathogenesis of AD, and Sal can slow the progression of AD by inhibiting pyroptosis. Subsequently, we established the D-gal and Nigericin-induced PC12 cells injury model in vitro to verify Sal blocks pyroptosis mainly by targeting the NLRP3 inflammasome. For in vivo studies, we observed that Aβ accumulation, Tau hyperphosphorylation, neurons of hippocampal damage, and cognitive dysfunction in AD mice, caused by bilateral injection of Aβ1-42 into the hippocampus and treatments with D-gal combine AlCl3. Besides, accumulated Aβ promotes NLRP3 inflammasome activation, which leads to the activation and release of a pro-inflammatory cytokine, interleukin-1 beta (IL-1β). Notably, both Aβ accumulation and hyperphosphorylation of Tau decreased and inhibited pyroptosis by downregulating the expression of IL-1β and IL-18, which can be attributed to the treatment of Sal. We further found that Sal can reverse the increased protein expression of TLR4, MyD88, NF-κB, P-NF-κB, NLRP3, ASC, cleaved Caspase-1, cleaved GSDMD, IL-1β, and IL-18 in vitro. The underlying mechanism may be through inhibiting TLR4/NF-κB/NLRP3/Caspase-1 signaling pathway. Our study highlights the importance of NLRP3 inflammasome-mediated pyroptosis in AD, and how the administration of pharmacological doses of Sal can inhibit NLRP3 inflammasome-mediated pyroptosis and ameliorate AD. Thus, we conclude that NLRP3 inflammasome-mediated pyroptosis plays a significant role in AD and Sal could be a therapeutic drug for AD.

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“…Traditionally, caspase activation has been defined as firstly recognizing the substrates’ tetrapeptide, XXXD (D is aspartic acid, X is other amino acid), and then cutting the specific peptide bond after D. The research of Feng Shao found that the recognition of GSDMD by caspase did not depend on the sequence characteristics of the tetrapeptide, but specifically directly recognized the C-terminal domain of GSDMD ( Wang K. et al, 2020 ). Studies have found that the expression level of GSDMD in the cerebrospinal fluid of AD patients was significantly higher than that of the general control group, and positively related to the release level of inflammatory factors, implying GSDMD could basically be applied as a diagnostic index of AD ( Shen et al, 2021 ). Other than GSDMD, recently, researches confirmed that GSDME also activated pyroptosis.…”

Section: Pyroptosismentioning

confidence: 99%

Research Progress of Pyroptosis in Alzheimer’s Disease

Xue

Cui

Qiu

2022

Front. Mol. Neurosci.

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Alzheimer’s disease (AD) is a disease characterized by insidious and progressive neurodegeneration, with clinical syndromes of memory and visuospatial skills damage. The pathogenic mechanism of AD is complex in which neural inflammation and neuron death play important roles. Pyroptosis, an inflammatory programmed cell death, has been reported to be involved in neuron death. Pyroptosis is executed by the protein family of gasdermins which punch pores on plasma membrane when activated by the upstream signals including the activation of NLRP3 and caspases, and subsequently triggers the inflammatory cascades featured by the release of interleukin (IL) -1β and IL-18. Herein, we summarized the current research on the roles of neuron pyroptosis in AD, aiming to provide a comprehensive view of the molecular mechanisms underlying AD pathogenesis and potential therapeutic targets for AD.

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Pyroptosis executive protein GSDMD as a biomarker for diagnosis and identification of Alzheimer’s disease

Cited by 42 publications

References 26 publications

Tau aggregation and its relation to selected forms of neuronal cell death

Tau aggregation and its relation to selected forms of neuronal cell death

Salidroside Ameliorates Alzheimer's Disease by Targeting NLRP3 Inflammasome-Mediated Pyroptosis

Research Progress of Pyroptosis in Alzheimer’s Disease

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