Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice

Abstract

Although the causal relationship between Alzheimer’s disease (AD) and iron overload remains unclear, iron dyshomeostasis or improper transport mechanisms are speculated to lead to the accumulation of this neurotoxic metal in the hippocampal formation and other cerebral areas related to neurodegenerative diseases, resulting in the formation of reactive oxygen species (ROS) and, ultimately, cell death. In this study, exposure to high dietary iron (HDI) revealed no significant difference in the number of iron-positive cells and iron content in the cortex and hippocampal region between wild-type (WT) and APP/PS1 mice; however, compared with the control mice, the HDI-treated mice exhibited upregulated divalent metal transporter 1 (DMT1) and ferroportin (Fpn) expression, and downregulated transferrin receptor (TFR) expression. Importantly, we confirmed that there were significantly fewer NeuN-positive neurons in both APP/PS1 and WT mice given HDI, than in the respective controls. Moreover, this iron-induced neuron loss may involve increased ROS and oxidative mitochondria dysfunction, decreased DNA repair, and exacerbated apoptosis and autophagy. Although HDI administration might trigger protective antioxidant, anti-apoptosis, and autophagy signaling, especially in pathological conditions, these data clearly indicate that chronic iron exposure results in neuronal loss due to apoptosis, autophagy, and ferroptosis, hence increasing the risk for developing AD.

Ferroptosis Mechanisms Involved in Neurodegenerative Diseases

“…After treatment with high dietary iron (HDI), WT (wild type) mice and the APP/PS1 double Tg mouse model of ADon (HDI) showed upregulation of divalent metal transporter 1 (DMT1) and ferroportin expression, and downregulation of TFR1 expression, with fewer NeuN-positive neurons in both animal models. Moreover, the iron-induced neuron loss may involve increased ROS production and oxidative mitochondria dysfunction, decreased DNA repair, and exacerbated apoptosis and autophagy [ 169 ]. Using X-ray spectromicroscopy and electron microscopy it was found that the coaggregation of Aβ and ferritin resulted in the conversion of the ferritin inert ferric core into more reactive low oxidation states [ 170 ].…”

Novel insights into ferroptosis: Implications for age-related diseases

“…Iron accumulation leads to nerve cell damage in patients with AD, likely by potentiating GSH loss 133 and iron deposition results in lipid peroxidation in cells, causing ferroptotic cell death. A recent study demonstrated that following treatment with high dietary iron, expression levels of ferroptosis-related antioxidants, including SLC7A11, GPX4, and superoxide dismutase in the brain, were decreased in APP/PS1 mice (a transgenic mice model of AD), suggesting that iron-induced neuron loss might occur through ferroptosis 134 . Therefore, chelating iron ions may have a therapeutic effect on AD by inhibiting ferroptosis.…”

Emerging Approaches to Investigate the Influence of Transition Metals in the Proteinopathies

“…In this context, it is of fundamental importance to consider the interplay between metals and peptides. It is well-established that amyloid β and α-synuclein deposits in human brain tissue are associated with metal accumulations, and these metals can affect the aggregation kinetics of amyloidogenic peptides and proteins through the induction of conformational change and/or metal-catalysed oxidation of the protein backbone [11,12,13,14,15,16,17,18,19,20,21,22,23]. It has been postulated that binding of metallic counter-ions neutralises charge repulsion, permitting the formation of more compact and structured conformations, such as those that comprise filamentous Lewy bodies [23].…”