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.
Highlights
Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder characterized by memory loss and language deterioration, and its incidence rate ranks first globally (Alzheimer’s Association, 2021)
This study aimed to investigate the interaction between AD and nod-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis via established Aβ1-42, D-gal/Aluminum chloride (AlCl3) mouse models in vivo, and a D-gal, Nigericin treated PC12 cells damage model in vitro
Our result indicates that Sal significantly offset the increase of IL-1β and IL-18 expression induced by Aβ142 and inhibited the expression of the pyroptosis-related protein, namely, NLRP3, apoptosisassociated speck-like protein (ASC), cleaved Caspase-1, cleaved Gasdermin D (GSDMD), IL-1β, and IL-18, its mechanism may act by inhibiting the NLRP3/caspase-1 signaling pathway
Summary
Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder characterized by memory loss and language deterioration, and its incidence rate ranks first globally (Alzheimer’s Association, 2021). The World Alzheimer Report 2021 reported that 50 million people worldwide have dementia. It is estimated that those suffering from dementia will grow from 55 to 139 million people during the period 2019–2050 (World Alzheimer Report 2021, 2021). Β-Amyloid (Aβ) deposits, Tau proteins hyperphosphorylated, and neuroinflammation are neuropathological hallmarks in AD (Emre et al, 2021). According to the hypothesis of Aβ, on the one hand, the aggregation of Aβ can initiate a cascade of reactions, including triggering hyperphosphorylation of Tau to form neurofibrillary tangles (NFTs), neuroinflammation, and neuronal degeneration, contributing to the onset of AD (Zhou and Fukushima, 2020). Death neuronal is a root reason for AD and other neurodegenerative diseases (Hambright et al, 2017). 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)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
