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

Abstract

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.

NLRP3/Caspase-1-Mediated Pyroptosis of Astrocytes Induced by Antipsychotics Is Inhibited by a Histamine H1 Receptor-Selective Agonist

“…Furthermore, we have demonstrated the involvement of NLRP3 signaling in antipsychotic-induced astrocyte death. Recent findings have revealed that pharmacological blockade of NLRP3 signaling by using salidroside, Dl-3-n-butylphthalide (NBP), gliquidone, or dimethyl fumarate significantly inhibited astrocyte-mediated neuroinflammation, reduced mitochondrial impairment, improved neuronal survival, and slowed the progression of various disease ( Cai et al, 2021 ; Kim et al, 2021 ; Que et al, 2021 ; Tastan et al, 2021 ). Therefore, we suggest that inhibition of NLRP3 signaling may help suppress antipsychotic-induced inflammation and astroglia death.…”

“…Pyroptosis has received increased attention due to its involvement in the pathogenesis of various severe diseases such as Alzheimer’s disease, Parkinson’s disease, atherosclerosis, cancer, osteoarthritis, and stroke ( An et al, 2020 ; Cai et al, 2021 ; Li et al, 2021b ; Liu et al, 2021 ; Wang et al, 2021 ; Romero et al, 2022 ). Pyroptosis is a proinflammatory programmed cell death, characterized by the formation of inflammatory bodies, the activation of caspases, the formation of membrane pores, and the release of proinflammatory factors such as interleukin 1β (IL-1β) ( Yang et al, 2015 ; Wu et al, 2019 ; Ma et al, 2021 ).…”

“…In pyroptotic signaling, NLRP3 is the most widely studied NLRP and has been reported to be related to various inflammatory diseases ( Yang et al, 2021 ; Yu et al, 2021 ). Activation of NLRP3 induces the release of IL-1β in the CNS ( Cai et al, 2021 ; Tastan et al, 2021 ), while inhibition of NLRP3 stops IL-1β production, reduces pyroptosis in the CNS, and improves cognitive function ( Cai et al, 2021 ; Tastan et al, 2021 ). Moreover, the NLRP3 inflammasome is expressed by astrocytes and is involved in astrocyte dysfunction and the inflammatory response ( Johann et al, 2015 ; Zhu and Tang, 2020 ).…”

Punicalagin Attenuates LPS-Induced Inflammation and ROS Production in Microglia by Inhibiting the MAPK/NF-κB Signaling Pathway and NLRP3 Inflammasome Activation

“… 8 Inhibition of NLRP3 inflammasome activation has been considered as a therapeutic strategy for ameliorating the progression of Alzheimer’s disease. 9–11 …”

Inhibitory Effect of Trihydroxy Isoflavone on Neuronal Apoptosis in Natural Aging Rats

“…It was found that NLRP3 inflammatory vesicle activation was significantly increased in hippocampal tissue of decompensated rats, and the protein expression of inflammatory factors was also markedly raised, and the apoptosis of neuronal cells was significantly raised. Lee et al found that toxic β-amyloid activates NLRP3 inflammatory vesicles and leads to AD pathology and tissue damage [19], and inhibition of Caspase-1 reduces the activation of RAW264.…”