Hepcidin/Ferroportin1 axis activation and astrocytic-neuronal crosstalk in brain during aging
Authors:
Mariarosa Mezzanotte (1), Giorgia Ammirata (2), Marina Boido (1), Antonella Roetto (3), Serena Stanga (1)
Organisations:
1: Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience Rita Levi Montalcini, University of Turin, Italy
2: Molecular Biotechnology Center Guido Tarone, University of Turin, Italy
3: Department of Clinical and Biological Sciences, University of Turin, Italy
Presenting author:
Mariarosa Mezzanotte
Exposition date:
Saturday, September 16, 2023
Exposition position:
006/2
During aging the accumulation of nonheme iron occurs in specific areas of the brain vulnerable to neurodegeneration. Typical aging features including increased Brain Blood Barrier (BBB) permeability, neuroinflammation, and oxidative stress cause iron redistribution and imbalance in the cerebral cortex. Therefore, it becomes urgent to investigate the mechanisms driving iron dyshomeostasis in the context of aging, and age-related diseases.
In this study, conducted in C57BL/6 mice during physiological aging by western blotting we measured a gradual reduction of the amount of Zonula occludens1, a tight junction protein of the BBB, indicative of a loss of BBB integrity. As consequence, the altered permeability of the BBB favours the income of iron in the brain. Indeed, in the cerebral cortex we found iron overload, demonstrated by Prussian blue Perl’s staining, accompanied by the increase of the expression of inflammatory and antioxidant genes (SAA1 and Nfr2), and reactive astrocytes and microglia verified by immunohistochemistry.
Interestingly, we observed that Hepcidin (Hepc), the iron-regulating peptide hormone produced mainly by hepatocytes, is expressed and upregulated in the aged brain in response to iron overload. Consequently, we found also that Ferroportin1 (Fpn1), the only iron exporter and target of Hepc, is downregulated in old mice cortexes, causing iron retention within neurons. Indeed, by immunohistochemistry, we observed that the iron exporter Fpn1 is expressed mainly by astrocytes, while the iron storage protein ferritin accumulates within neurons. These observations showed that the Hepc/Fpn1-axis is also active in the brain during aging. Moreover, we demonstrated for the first time that iron accumulation within neurons is due to the activation of a selective form of autophagy mediated by NCOA4, termed “ferritinophagy”.
Overall, our data highlight new regulators of brain iron and potential targets in the prevention of oxidative damage, stress, and neurodegeneration.
