Ferroptosis, a Potential Therapeutic Target in Alzheimer's Disease.

Kai Chen,Wendai Bao,Xianming Cao,Xiaobing Jiang,Ling-Qiang Zhu,Moxin Wu

doi:10.3389/fcell.2021.704298

Abstract

Cell death is a common phenomenon in the progression of Alzheimer’s disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. Moreover, several hallmarks of AD pathogenesis were consistent with the characteristics of ferroptosis, such as excess iron accumulation, elevated lipid peroxides, and reactive oxygen species (ROS), reduced glutathione (GSH), and glutathione peroxidase 4 (GPX4) levels. Besides, some ferroptosis inhibitors can relieve AD-related pathological symptoms in AD mice and exhibit potential clinical benefits in AD patients. Therefore, ferroptosis is gradually being considered as a distinct cell death mechanism in the pathogenesis of AD. However, direct evidence is still lacking. In this review, we summarize the features of ferroptosis in AD, its underlying mechanisms in AD pathology, and review the application of ferroptosis inhibitors in both AD clinical trials and mice/cell models, to provide valuable information for future treatment and prevention of this devastating disease.

Highlights

Ferroptosis is a recently defined iron-dependent form of cell death induced by the small molecule erastin (Dixon et al, 2012)
MDA, isoprostanes, and 4HNE were most promising and consistent between different studies (Pena-Bautista et al, 2019). These findings indicated that the accumulated lipid peroxides contribute to the neuropathology of Alzheimer’s disease (AD), and some lipid peroxidation products can act as the biomarkers for AD diagnosis and prognosis
A fatty acid synthase inhibitor, CMS121, protects against ferroptosis-induced lipid peroxidation and alleviates cognitive impairment in amyloid-beta precursor protein (APP)/PS1transgenic mice (Ates et al, 2020). These findings demonstrated that restoration of lipid peroxidation effectively rescued the AD-like symptoms and lipid metabolism pathway will be a potential therapeutic target for the prevention of this disease in the future

Summary

Introduction

Ferroptosis is a recently defined iron-dependent form of cell death induced by the small molecule erastin (Dixon et al, 2012). The levels of miR-124, which directly induced a posttranscriptional deregulation of Fpn, increased in AD patients; (2) Iron accumulation aggravated toxic Aβ deposition and tau hyperphosphorylation, which disrupted GSH synthesis and reduced Gpx4 levels (3); (4) Elevated LOX catalyzed PUFAs and generated ROS via Fenton reaction.

Results

Conclusion