TTP488 ameliorates NLRP3-associated inflammation, viability, apoptosis, and ROS production in an Alzheimer's disease cell model by mediating the JAK1/STAT3/NFκB/IRF3 pathway.

Abstract

Alzheimer's disease (AD), the most prevalent dementia, is identified as a neurodegenerative disease arising from a degenerative disturbance in the central nervous system. A previous study reported that TTP488 could ameliorate symptoms in patients with mild AD, but the underlying mechanisms need to be studied further. Therefore, the objective of this study was to explore the role of TTP488 in the development of an AD cell model. Administration of TTP448 in an AD cell model reduced the expression of pro-inflammatory cytokines [interleukin (IL)-1β, IL-6, and TNF-α], reversed the inhibitory role of Aβ on cell proliferation and viability, and decreased Aβ-triggered cell apoptosis and reactive oxygen species (ROS) production. Furthermore, Aβ treatment induced activation of JAK1/STAT3/NFκB/IRF3 pathway as well as NLRP3 expression, and TTP488 administration partially reversed the activation of this pathway and NLRP3 expression. Use of WP1160, a STAT3 agonist, re-activated the downstream STAT3/NFκB/IRF3 pathway and NLRP3 expression. Moreover, we found that WP1160 counteracted the role of TTP488 in Aβ-induced SH-SY5Y cells' viability, inflammation, apoptosis, and ROS production. SIGNIFICANCE OF THE STUDY: This study explores the role of TTP488 in the development of an Alzheimer's disease (AD) cell model and confirms that TTP488 administration notably promotes cell proliferation and reduces apoptosis, inflammatory factor expression, and reactive oxygen species generation. Further, this study suggests that the NLRP3-relevant JAK1/STAT3/P65/IRF3 signalling pathway is related to AD pathogenesis.