High Iron and Iron Household Protein Contents in Perineuronal Net-Ensheathed Neurons Ensure Energy Metabolism with Safe Iron Handling

Int J Mol Sci. 2022 Jan 31;23(3):1634. doi: 10.3390/ijms23031634.


A subpopulation of neurons is less vulnerable against iron-induced oxidative stress and neurodegeneration. A key feature of these neurons is a special extracellular matrix composition that forms a perineuronal net (PN). The PN has a high affinity to iron, which suggests an adapted iron sequestration and metabolism of the ensheathed neurons. Highly active, fast-firing neurons-which are often ensheathed by a PN-have a particular high metabolic demand, and therefore may have a higher need in iron. We hypothesize that PN-ensheathed neurons have a higher intracellular iron concentration and increased levels of iron proteins. Thus, analyses of cellular and regional iron and the iron proteins transferrin (Tf), Tf receptor 1 (TfR), ferritin H/L (FtH/FtL), metal transport protein 1 (MTP1 aka ferroportin), and divalent metal transporter 1 (DMT1) were performed on Wistar rats in the parietal cortex (PC), subiculum (SUB), red nucleus (RN), and substantia nigra (SNpr/SNpc). Neurons with a PN (PN+) have higher iron concentrations than neurons without a PN: PC 0.69 mM vs. 0.51 mM, SUB 0.84 mM vs. 0.69 mM, SN 0.71 mM vs. 0.63 mM (SNpr)/0.45 mM (SNpc). Intracellular Tf, TfR and MTP1 contents of PN+ neurons were consistently increased. The iron concentration of the PN itself is not increased. We also determined the percentage of PN+ neurons: PC 4%, SUB 5%, SNpr 45%, RN 86%. We conclude that PN+ neurons constitute a subpopulation of resilient pacemaker neurons characterized by a bustling iron metabolism and outstanding iron handling capabilities. These properties could contribute to the low vulnerability of PN+ neurons against iron-induced oxidative stress and degeneration.

Keywords: DMT1; MTP1; brain; cellular quantification; ferritin H/L; iron; iron proteins; neurodegeneration; perineuronal net; transferrin; transferrin receptor.

MeSH terms

  • Animals
  • Apoferritins / metabolism
  • Cation Transport Proteins / metabolism
  • Energy Metabolism
  • Gene Expression Regulation
  • Iron / metabolism*
  • Iron-Binding Proteins / metabolism*
  • Male
  • Peripheral Nerves / metabolism*
  • Rats
  • Rats, Wistar
  • Receptors, Transferrin / metabolism
  • Transferrin / metabolism


  • Cation Transport Proteins
  • Iron-Binding Proteins
  • Receptors, Transferrin
  • Tfrc protein, rat
  • Transferrin
  • metal transporting protein 1
  • solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
  • Apoferritins
  • Iron