PIAS3 suppresses damage in an Alzheimer\u2019s disease cell model by inducing the STAT3-associated STAT3/Nestin/Nrf2/HO-1 pathway

Chen Li,Qiaoya Ma,Ruili Wang,Youyou Zhang,Chunting Hu

doi:10.1186/s10020-021-00410-3

Abstract

BackgroundAlzheimer’s disease (AD), the most common form of dementia, is caused by the degeneration of the central nervous system (CNS). A previous study reported that signal transducer and activator of transcription 3 (STAT3) is activated during AD development; nonetheless, the related mechanism remains unknown. Thus, this study used a cell model to explore whether and how the protein inhibitor of activated STAT3 (PIAS3) is involved in AD development.MethodsCerebrospinal fluid (CSF) specimens of 30 patients with AD and 10 normal participants were included in this study. SH-SY5Y cells were used to constructed AD model. Relevant indices were then detected and analyzed.ResultsThe results showed that compared with the control group, PIAS3 expression was substantially decreased in patients with AD and amyloid beta (Aβ)-treated SH-SY5Y cells. PIAS3 overexpression was able to reverse the detrimental effects of Aβ treatment on cell survival and growth. Further, it could also ameliorate apoptosis and oxidative stress in Aβ-treated SH-SY5Y cells. Additionally, PIAS3 was shown to reduce the activated form of STAT3 and increase the activity of the downstream Nestin/nuclear factor erythroid 2-related factor/heme oxygenase-1 pathway.ConclusionsSTAT3 reactivation by colivelin treatment negated the influence of PIAS3 on the survival, growth, apoptosis, and oxidative stress of Aβ-treated SH-SY5Y cells.

Highlights

Alzheimer’s disease (AD), the most common form of dementia, is caused by the degeneration of the central nervous system (CNS)
Different protein inhibitor of activated STAT3 (PIAS3) expression in patients with AD and model Cerebrospinal fluid (CSF) samples were obtained from patients with AD and utilized for PIAS3 expression analysis
Reduced expression of PIAS3 mRNA in AD cell model was observed in a dose- and time-dependent manner, at both mRNA and protein levels (Fig. 1B– E)

Summary

Introduction

Alzheimer’s disease (AD), the most common form of dementia, is caused by the degeneration of the central nervous system (CNS). This study used a cell model to explore whether and how the protein inhibitor of activated STAT3 (PIAS3) is involved in AD development. Neuropathological analyses have indicated an increase in STAT3 Tyr705 phosphorylation in the hippocampi of patients with AD (Guillemaud et al 2020; Wan et al 2010) and marked upregulation of phosphor-STAT3 in APP/PS1 transgenic mice (Wan et al 2010). This STAT3 activation might induce astrocyte reactivity (Guillemaud et al 2020), which might decrease ameliorated memory loss (Ceyzériat et al 2018; Reichenbach 2019). STAT3 phosphorylation plays a role in the release of cytokines relevant to AD neuroinflammation, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β (Samavati et al 2009)

Methods

Results

Conclusion