Iron chelators as a therapeutic option for Alzheimer’s disease—A mini-review

Abstract

Neurodegenerative disorders, particularly Alzheimer’s disease (AD), remain a great challenge regarding the finding of effective treatment, one main reason being the incomplete understanding of their etiology. With many intensely debated hypotheses, a newer approach based on the impact of iron imbalance in sustaining neurodegeneration in the central nervous system becomes increasingly popular. Altered iron homeostasis leads to increased iron accumulation in specific brain areas, explaining the clinical picture of AD patients. Moreover, growing evidence sustains the significant impact of iron metabolism in relationship to other pathological processes encountered in the AD-affected brain, such as the amyloidogenic pathway, chronic inflammation, or oxidative stress. In this context, this mini-review aims to summarize the novel data from the continuously expanding literature on this topic in a didactic manner. Thus, in the first part, the authors briefly highlight the most relevant aspects related to iron absorption, transport, regulation, and elimination at the cerebral level, focusing on the role of the blood-brain barrier and the newer concept of ferroptosis. Subsequently, currently available iron chelation therapies are discussed, including an overview of the most relevant clinical trials on this topic. In the final part, based on the latest results from in vitro and in vivo studies, new research directions are suggested to enhance the development of effective antidementia therapies.

Could Alcohol-Related Cognitive Decline Be the Result of Iron-Induced Neuroinflammation?

“…A recent review involving two iron chelating agents, M30 and HLA20, suggested the neuroprotective role of iron-chelating agents in animal models by reducing neurodegenerative pathology, upregulating signalling pathways that provide neuronal protection, and providing positive behavioural modification [ 37 ]. Several studies have recently proposed the utilisation of iron-chelating agents for the treatment of Alzheimer’s disease [ 62 , 64 ]. Another study used alpha-lipoic acid in transgenic mice models, which prevented tau-hyperphosphorylation and reduced oxidative stress, inflammation, and ferroptosis in neuronal cells [ 65 ].…”

Intracellular iron accumulation facilitates mycobacterial infection in old mouse macrophages

“…In the context of aging, iron chelation therapy is a topic of interest due to the potential role of iron accumulation in age-related diseases and conditions. Iron chelating drugs are being explored as a potential therapeutic strategy to manage neurodegenerative diseases and age-related diseases, such as Alzheimer’s disease [ 44 ]. Our results show for the first time that deferoxamine improved M. avium killing in BMMs from old mice in cell culture (Fig.…”

Targeting Biometals in Alzheimer’s Disease with Metal Chelating Agents Including Coumarin Derivatives

“…DFO binds iron in a 1:1 ratio and is a hexadentate ligand [ 44 ]. Although being the most popular iron chelator with more than 30 years of clinical experience [ 45 ], DFO application is limited by its short half-life and the need to be administered intravenously or subcutaneously [ 46 ]. Some studies have, however, validated the use of intranasal DFO with the aim of reversing iron-induced memory problems by inhibition of Aβ aggregation, neuronal ferroptosis, τ phosphorylation, and aberrant APP cleavage in AD mouse models [ 47 – 50 ].…”