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bioRxiv · 10.1101/2021.07.01.450665

BBB damage in aging causes brain iron deposits via astrocyte-neuron crosstalk and Hepc/Fpn1 pathway

Mezzanotte, M.·Ammirata, G.·Boido, M. M.·Stanga, S.·Roetto, A.
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Abstract

During aging, iron accumulates in brains regions vulnerable to neurodegeneration: the cerebral cortex and the hippocampus. However, the mechanism of iron regulation in the brain remains scarce. Here, we demonstrated for the first time the involvement of the Hepcidin/Ferroportin1 pathway in brain iron metabolism during aging. We demonstrated the alteration of BBB integrity, that leads to increased iron permeability and deregulation of iron homeostasis during aging. We found that brain iron overload drives Hepcidin upregulation and, consequently, the inhibition of the iron exporter Ferroportin1, neuroinflammation and oxidative stress. Moreover, both in the cerebral cortex and hippocampus Ferroportin1 colocalizes with astrocytes, while the iron storage protein ferritin light-chain with neurons. This differential distribution suggests that astrocytes mediate iron shuttling and neurons are unable to metabolize it. Furthermore, we observed NCOA4-dependent ferritinophagy of ferritin heavy-chain isoforms determining the increase of light-chain enriched ferritin heteropolymers that are more efficient as iron chelators. Altogether, these data highlight the involvement of the Hepcidin/Ferroportin1 axis and NCOA4 during mice aging as a response to a higher iron influx to the brain.

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Mezzanotte, M., Ammirata, G., Boido, M. M., Stanga, S., Roetto, A.. 2021-07-01. BBB damage in aging causes brain iron deposits via astrocyte-neuron crosstalk and Hepc/Fpn1 pathway. https://doi.org/10.1101/2021.07.01.450665

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