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. 2019 Feb 24;8(2):198.
doi: 10.3390/cells8020198.

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

Lin-Bo Li  1 , Rui Chai  2 , Shuai Zhang  3 , Shuang-Feng Xu  4 , Yan-Hui Zhang  5 , Hai-Long Li  6 , Yong-Gang Fan  7 , Chuang Guo  8
Affiliations

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

Lin-Bo Li et al. Cells. .

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.

Keywords: Alzheimer’s disease; apoptosis; autophagy; ferroptosis; iron; neuron loss.

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Conflict of interest statement

The authors declare that no conflict of interests.

Figures

Figure 1
Figure 1
Effect of high dietary iron on iron and iron-transport-related proteins in the mouse brain. (A) Perl’s diaminobenzidine (DAB) iron staining showed that high dietary iron (HDI) could increase the number of iron-positive cells in the cortex and hippocampal region of wild-type (WT) and APP/PS1 mice. (B) Quantitative analyses of Perl’s-DAB iron staining. Scale bar = 50 μm. (C) The results of iron atomic absorption spectroscopy (AAS). (D, E) Western blot analysis of transferrin receptor (TFR), divalent metal transporter 1 (DMT1) and ferroportin (Fpn). (D1–D3, E1–E3) Quantitative analyses of Western blot for TFR, DMT1 and Fpn. β-actin was used as an internal control. All results are presented as the mean ± standard error of the mean (SEM) (n = 8). * p < 0.05, ** p < 0.01 compared with the control group.
Figure 2
Figure 2
(A) Immunofluorescence of Aβ and NeuN. Scale bar = 25 μm, (A1,A2) Quantitative analyses of Neun-positive staining and Aβ-positive staining. (B) Nissl staining in the mouse brain. Scale bar = 25 μm. (B1) Quantitative analyses of Nissl-positive staining, n = 8. * p < 0.05, ** p < 0.01 compared with the control group; # p < 0.05 compared with the iron-treated WT group.
Figure 3
Figure 3
Effect of HDI on neurons and glia. (A, B) Western blot analysis of NeuN, glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1). (A1–A3, B1–B3) Quantitative analyses of Western blot for NeuN, GFAP and Iba1. β-actin was used as an internal control. (C, D) Immunohistochemistry staining of GFAP and Iba1. (C1, D1) Quantitative analyses of GFAP-positive astrocytes staining and Iba1-positive microglia staining. Scale bar = 50 μm. All results are presented as the mean ± SEM (n = 8). * p < 0.05, ** p < 0.01 compared with the control group; # p < 0.05, # # p < 0.01 compared with the iron-treated WT group.
Figure 4
Figure 4
HDI-induced redox status in the mouse brain. (A, B) Western blot analysis of glutamate-cystine transporter (xCT), glutathione peroxidase 4 (GPX4), and superoxide dismutase (SOD1). (A1–A3, B1–B3) Quantitative analyses of Western blot for xCT, GPX4, and SOD1. β-actin was used as an internal control. (A4, A5, B4, B5) Quantitative analyses of reactive oxygen species (ROS) and malondialdehyde (MDA). All results are presented as the mean ± SEM (n = 8). * p < 0.05, ** p < 0.01.
Figure 5
Figure 5
HDI-induced oxidative DNA damage in the mouse brain. (A, B) Western blot analysis of MutY homologous DNA glycosidase (MUTYH), 8-hydroxyguanine DNA glycosidase (OGG1), and 8-hydroxy guanine nucleotidase (MTH1). (A1–A3, B1–B3) Quantitative analyses of Western blot for MUTYH, OGG1, and MTH1. β-actin was used as an internal control. All results are presented as the mean ± SEM (n = 8). ** p < 0.01.
Figure 6
Figure 6
Changes in apoptosis-related proteins in the brains of HDI-treated mice. (A, B) Western blot analysis of PARP1, caspase 3, Bcl2, Bax, and AIF. (A1–A6, B1–B6) Quantitative analyses of Western blot for PARP1, caspase 3, Bcl2, Bax and AIF. β-actin was used as an internal control. All results are presented as the mean ± SEM (n = 8). * p < 0.05, ** p < 0.01.
Figure 7
Figure 7
Changes in autophagy-related proteins in the brains of HDI-treated mice. (A, B) Western blot analysis of m-TOR, p-m-TOR, calpain 1, beclin 1, LC3 A/B, and P62. (A1–A6, B1–B6) Quantitative analyses of Western blot for m-TOR, p-m-TOR, calpain 1, beclin 1, LC3 A/B, and P62. β-actin was used as an internal control. All results are presented as the mean ± SEM (n = 8). * p < 0.05, ** p < 0.01.
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