Iron dyshomeostasis and ferroptosis in Alzheimer’s disease: Molecular mechanisms of cell death and novel therapeutic drugs and targets for AD

Abstract

Alzheimer’s disease (AD) is a degenerative disease of the central nervous system that is the most common type of senile dementia. Ferroptosis is a new type of iron-dependent programmed cell death identified in recent years that is different from other cell death forms. Ferroptosis is induced by excessive accumulation of lipid peroxides and reactive oxygen species (ROS) in cells. In recent years, it has been found that ferroptosis plays an important role in the pathological process of AD. Iron dyshomeostasis contribute to senile plaques (SP) deposition and neurofibrillary tangles (NFTs). Iron metabolism imbalance in brain and the dysfunction of endogenous antioxidant systems including system Xc- and glutathione peroxidase (GPX) are closely related to the etiopathogenesis of AD. Dysfunction of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy induced ferroptosis can accelerates the pathological process of AD. In addition, NRF2, through regulating the expression of a considerable number of genes related to ferroptosis, including genes related to iron and glutathione metabolism, plays an important role in the development of AD. Here, we review the potential interaction between AD and ferroptosis and the major pathways regulating ferroptosis in AD. We also review the active natural and synthetic compounds such as iron chelators, lipid peroxidation inhibitors and antioxidants available to treat AD by alleviating iron dyshomeostasis and preventing ferroptosis in mice and cell models to provide valuable information for the future treatment and prevention of AD.

A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer's disease

“…20,21 Patients with mild cognitive impairment (MCI) and high amyloid plaque loads exhibit an increase in cortical iron accumulation, which heightens the risk of AD. 22 Ferroptosis, a form of regulated cell death, has been implicated in the development of AD, characterized by iron-driven lipid peroxidation and glutamate excitotoxicity in the brain tissues of AD patients and models. Cerebrospinal fluid (CSF) ferritin levels have been found to be inversely associated with MCI and AD, with the Alzheimer's risk allele APOE-ε4 increasing ferritin levels, indicating that iron imbalance may be a risk factor for AD.…”

Ex vivo investigation of betaine and boric acid function as preprotective agents on rat synaptosomes to be treated with Aβ (1–42)

“…These soluble Aβ oligomers can disrupt synaptic function and impair neurotransmission, leading to synaptic dysfunction and ultimately synapse loss. Moreover, increasing evidence suggests a connection between dysregulated brain iron and the progression of AD, and this dysregulation has been implicated in the mechanism of neurodegeneration known as ferroptosis 30,31 . Our results of the role of BA and betaine in synaptosomes treated with Aβ (1–42) has been expanded by biochemical analyses demonstrating that disruptions in synaptosomes function, either through lipid or DNA damages, make synaptosomes more susceptible to ferroptosis.…”

“…Moreover, increasing evidence suggests a connection between dysregulated brain iron and the progression of AD, and this dysregulation has been implicated in the mechanism of neurodegeneration known as ferroptosis. 30,31 Our results of the role of BA and betaine in synaptosomes treated with Aβ (1-42) has been expanded by biochemical analyses demonstrating that disruptions in synaptosomes function, either through lipid or DNA damages, make synaptosomes more susceptible to ferroptosis. For the first time in this study, we found that BA and betaine pre-treatment did not cause any morphological and biochemical changes in rat brain tissue.…”

Hydrogen sulfide alleviates beryllium sulfate‐induced ferroptosis and ferritinophagy in 16HBE cells

“…Iron is a trace metal essential to the human body and is essential for normal cell function. The main storage form of iron in cells is ferritin, when intracellular iron deficiency or iron demand increases, ferritin released through selective autophagy to provide bioavailable iron to maintain intracellular iron homeostasis (Masaldan et al, 2018; Tang et al, 2019; Y. Zhang, Wang, & Chang, 2022). Accumulating studies found that NCOA4 knockdown inhibited ferritin degradation, reduced iron accumulation and intracellular ROS in cancer cells and fibroblasts, and thus inhibited ferroptosis, whereas NCOA4 overexpression has the opposite effect (J. Liu, Zhang, et al, 2022; Mancias et al, 2015).…”

“…Iron is a trace metal essential to the human body and is essential for normal cell function. The main storage form of iron in cells is ferritin, when intracellular iron deficiency or iron demand increases, ferritin released through selective autophagy to provide bioavailable iron to maintain intracellular iron homeostasis (Masaldan et al, 2018;Tang et al, 2019;Y. Zhang, Wang, & Chang, 2022).…”