Changes in cellular ferritin distribution of human brain tissue during autolysis revealed using analytical electron microscopy

Abstract

Iron is known to accumulate in neurological disorders, so a careful balance of the iron concentration is essential for healthy brain functioning. An imbalance in iron homeostasis could arise due to the dysfunction of the proteins involved in iron homeostasis. Here, we focus on ferritin - the primary iron storage protein of the brain. Though it is known that glial cells and neurons differ in their concentration of ferritin, the change in the number of iron-filled ferritin cores or their distribution between different cell types during autolysis has not been revealed yet. Here, we show the cellular and region-wide distribution of ferritin in the human brain using state-of-the-art analytical electron microscopy. We validated the concentration of iron-filled ferritin cores to the absolute iron concentration measured by quantitative MRI and inductively coupled plasma mass spectrometry. We show that ferritins lost iron from their cores with progressing autolysis whereas the overall iron concentrations were unaffected. Though the highest concentration of ferritins was found in glial cells, we found that as the total ferritin concentration increased in a patient, ferritin accumulated more in neurons than in glial cells. Collectively our findings point out the unique behaviour of neurons in storing iron during autolysis and explain the differences between the absolute iron concentrations and iron-filled ferritin in a cell-type-dependent fashion in the human brain. Significance statementBalance of the iron load of the brain is crucial to preventing neurodegenerative disorders. Our study establishes a relation between autolysis, iron, and ferritin in the human brain with emphasis on the role of different cells in ferritin storage. We demonstrate that the iron load of ferritins does not correlate with mean iron concentrations during autolysis. Neurons retain more iron-loaded ferritin than glial cells with increasing ferritin count, which may make neurons more susceptible and exacerbate neuronal loss during iron overload. Neurons are also depleted of iron-loaded ferritin cores faster than glial cells during autolysis, demonstrating their unique role in iron storage. This paves the way to understanding the respective roles of neurons and glial cells in preventing or promoting neurodegeneration.