Prostaglandin I₂ Attenuates Prostaglandin E₂-Stimulated Expression of Interferon γ in a β-Amyloid Protein- and NF-κB-Dependent Mechanism.

Pu Wang,Ya-Nan Su,Pei-Pei Guan,Xin Yu,Zhan-You Wang,Li-Chao Zhang

doi:10.1038/srep20879

Abstract

Cyclooxygenase-2 (COX-2) has been recently identified as being involved in the pathogenesis of Alzheimer’s disease (AD). However, the role of an important COX-2 metabolic product, prostaglandin (PG) I2, in AD development remains unknown. Using mouse-derived astrocytes as well as APP/PS1 transgenic mice as model systems, we firstly elucidated the mechanisms of interferon γ (IFNγ) regulation by PGE2 and PGI2. Specifically, PGE2 accumulation in astrocytes activated the ERK1/2 and NF-κB signaling pathways by phosphorylation, which resulted in IFNγ expression. In contrast, the administration of PGI2 attenuated the effects of PGE2 on stimulating the production of IFNγ via inhibiting the translocation of NF-κB from the cytosol to the nucleus. Due to these observations, we further studied these prostaglandins and found that both PGE2 and PGI2 increased Aβ1–42 levels. In detail, PGE2 induced IFNγ expression in an Aβ1–42-dependent manner, whereas PGI2-induced Aβ1–42 production did not alleviate cells from IFNγ inhibition by PGI2 treatment. More importantly, our data also revealed that not only Aβ1–42 oligomer but also fibrillar have the ability to induce the expression of IFNγ via stimulation of NF-κB nuclear translocation in astrocytes of APP/PS1 mice. The production of IFNγ finally accelerated the deposition of Aβ1–42 in β-amyloid plaques.

Highlights

Alzheimer’s diseases (AD) is the most common cause of dementia in aged people and is characterized clinically by cognitive decline and pathologically by the accumulation of β -amyloid protein (Aβ ) and hyperphosphorylation of tau in the brain[1]
Due to previous studies suggesting that interferon γ (IFNγ) plays a critical role in the pathogenesis of AD21, we evaluated the expression levels of IFNγ in AD patients and APP/PS1 transgenic mice at 6 or 9 months of age
In line with these observations in AD patients, IFNγ immunostaining was highly enhanced in the cerebral cortex and dentate gyrus (DG) region of the hippocampus of APP/PS1 mice at 6 months of age when compared to wild type (WT) C57BL/6 mice (Fig. 1B)

Summary

Introduction

Alzheimer’s diseases (AD) is the most common cause of dementia in aged people and is characterized clinically by cognitive decline and pathologically by the accumulation of β -amyloid protein (Aβ ) and hyperphosphorylation of tau in the brain[1]. Wahlstrom et al.[15] reported that when compared to a placebo treatment, the administration of the PGI2 analogue epoprostenol significantly decreased C-reactive protein (CRP) and generally decreased IL-6 levels in patients with severe traumatic brain injury Following from this observation, Schuh et al.[16] reported that the early induction of PGI2 at the site of traumatic injury resulted in the aggregation of IL-1β -expressing macrophages as a critical cause of neuropathic pain. Apart from β -secretase, it has been reported that IFNγ production has the ability to accelerate γ -secretase cleavage of APP22 by upregulating the expression of presenillin 2 (PS2) in human neuronal cells[23] When considered together, these data prompted us to investigate the roles of PGE2 and PGI2 in regulating the expression of IFNγ during the course of AD development. PGE2 and PGI2 have opposing effects on IFNγ expression, which is responsible for accelerating Aβ 1–42 deposition in APs during the course of AD development

Methods

Results

Conclusion