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Brain iron transport and neurodegeneration

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Abstract

Despite years of investigation, it is still not known why iron levels are abnormally high in some regions of the brain in neurodegenerative disorders. Also, it is not clear whether iron accumulation in the brain is an initial event that causes neuronal death or is a consequence of the disease process. Here, we propose that iron and iron-induced oxidative stress constitute a common mechanism that is involved in the development of neurodegeneration. Also, we suggest that, at least in some neurodegenerative disorders, brain iron misregulation is an initial cause of neuronal death and that this misregulation might be the result of either genetic or non-genetic factors.

Section snippets

Transferrin-bound and non-transferrin-bound iron in the brain

The mechanisms of iron transport across the blood–brain barrier (BBB) have not yet been completely clarified. The accumulated evidence suggests that the transferrin–transferrin receptor (Tf–TfR) pathway might be the major route of iron transport across the luminal membrane of the capillary endothelium 7, 8, 9, and that iron, possibly in the form of Fe2+, crosses the abluminal membrane and enters the interstitial fluid (IF). However, the molecular events of this process are not known 7, 8 (Fig. 1

Initial cause or secondary consequence

Despite considerable investigation, it is still not clear whether excessive iron accumulation in the brain is an initial event that causes neuronal death or is a consequence of the disease process 2, 3. On the basis of current knowledge, however, it seems reasonable to propose that brain iron misregulation is an initial cause of neuron death in some, but not all, NDs. The evidence suggests that the abnormally increased iron levels in the brain could result from disruption in the production of

Conclusion

In this article, we suggest that, at least in some NDs, brain iron misregulation is an initial cause of neuronal death and that this misregulation might be led by either genetic or non-genetic factors. Also, we propose that iron and iron-induced oxidative stress constitute a common mechanism involved in the development of neurodegeneration. However, it should be pointed out that many relevant questions need to be clarified. The precise roles and mechanisms of iron transport proteins in brain

Outstanding questions

  • How many types of iron transport proteins are there in the brain, what is their cellular and regional distribution and what is their physiological importance in brain iron homeostasis?

  • How is the production of iron transport proteins controlled in the brain under physiological circumstances?

  • What are the genetic or non-genetic causes that might lead to misregulation of the production of brain iron transport proteins?

  • What is the transport form of iron across the abluminal part of the capillary

Acknowledgments

The studies in this laboratory were supported by Competitive Earmarked Grants from the HK Research Grants Council (A/C: 357/026-B-Q151 and 354/117-B-Q164) and HK Polytechnic University Grants (A/C: A-P136, A-PA79, A-PB48 and G12.xx.93A2).

References (46)

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