Investigation of the Iron Oxide Nanoparticle Effects on Amyloid Precursor Protein Processing in Hippocampal Cells

Abstract

Introduction: Iron oxide nanoparticles (Fe₂O₃-NPs) are small magnetic particles that are widely used in different aspects of biology and medicine in modern life. Fe₂O₃-NP accumulated in the living cells due to the absence of an active system to excrete the iron ions and damages cellular organelles by high reactivity.

Methods: Herein cytotoxic effects of Fe₂O₃-NP with a size of 50 nm on the primary culture of neonatal rat hippocampus were investigated using 2,5-diphenyltetrazolium bromide (MTT) assay. Pathophysiological signs of Alzheimer's disease such as amyloid precursor protein (APP) expression, Aβ aggregation, soluble APPα, and APPβ secretion were also investigated in hippocampal cells treated with various concentrations of nanoparticle (NP) for different exposure times.

Results: Our results revealed that Fe₂O₃-NP treatment causes oxidative stress in cells which is accompanied by upregulation of the APP and Aβ in a concentration-dependent manner. NP exposure also leads to more secretion of sAPPβ rather than sAPPα, leading to increased activation of β-secretase in NP-received cells. All the harmful effects accumulate in neurons that cannot be renovated, leading to neurodegeneration in Alzheimer's disease.

Conclusion: This study approved iron-based NPs could help to develop Alzheimer's and related neurological disorders and explained why some of the iron chelators have therapeutic potential in Alzheimer's disease.

Highlights: Fe₂O₃-NP induced oxidative stress in hippocampal cells in a concentration dependent manner.Fe₂O₃-NP imposed up-regulation of APP in hippocampal cells.Fe₂O₃-NP activated β-secretase and elevated sAPPβ/sAPPα ratio.Cumulative effects of Fe₂O₃-NP damages increased cell death in neurons.

Plain language summary: The most common type of dementia is Alzheimer's disease (AD), which is characterized by chronic neurodegeneration, impairment of memory, and disturbed planning, language, and thinking ability. In recent years, the use of nanoparticles has been increased in all aspects of life. Among these nanoparticles, iron oxide nanoparticles (Fe₂O₃-NP) are vital in biological sciences, medicine, magnetic resonance imaging, ultrasound, and optical imaging. Considering the general application and high reactivity of iron, growing concerns exist about the Fe₂O₃-NP application harms, especially in the central nervous system. Hippocampus tissue is one of the affected tissues in AD, which is widely investigated in recent years. This study aimed to investigate the cytotoxic effects of Fe₂O₃-NP on the primary culture of the hippocampus as one of the main tissues damaged in patients with AD. Our results revealed that treatment with different concentrations of Fe₂O₃-NP caused cellular damage in hippocampal cells. Exposure to Fe₂O₃-NP also caused oxidative stress. Our results showed a close association between oxidative stress and AD's pathological symptoms. The Fe₂O₃-NP application in medicine and biology should be limited.

Keywords: Amyloid precursor protein (APP); Aβ deposition; Hippocampal cells; Neurodegeneration; Oxidative stress.