Abstract
During aging, iron accumulates in brain’s 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.
Abbreviations
- ATP
- adenosine triphosphate
- ROS
- Reactive Oxidative Species
- Tf
- Transferrin
- TfR1
- Transferrin Receptor 1
- DMT1
- Divalent Metal Transporter 1
- Fpn1
- Ferroportin 1
- Ft-H
- Ferritin heavy chain
- Ft-L
- Ferritin light chain
- Hep
- Hepcidin
- BBB
- Blood Brain Barrier
- Tf-Fe2
- Transferrin iron complex
- BMVECs
- Brain microvascular endothelial cells
- CNS
- Central Nervous System
- IRPs
- Iron Regulatory Proteins
- NEO-1
- Neogenin-1
- BI
- Brain Iron
- miRNA
- MicroRNAs
- NDs
- Neurodegenerative disorders
- PD
- Parkinson’s disease
- AD
- Alzheimer disease
- MS
- Multiple sclerosis
- NCOA4 or ARA70
- Nuclear Receptor Coactivator 4 or Androgen Receptor (AR) Coactivator
- HERC2
- E3 ubiquitin protein ligase
- SD
- Standard Diet
- Nfr2
- Nuclear factor Erythroid 2-related factor 2
- SAA1
- Serum Amyloid A1
- Gus-β
- β-glucuronidase
- ZO-1
- Zonula Occludens-1
- GFAP
- Glial Fibrillary Acidic Protein
- MAP-2
- Microtubule-Associated Protein 2
- VGLUT1
- Vesicular Glutamate Transporter 1
- GLAST
- Glutamate Transporter
- IBA-1
- Ionized calcium-binding adaptor molecule 1
- NDS
- normal donkey serum
- DAPI
- 4,6-diamidino-2-phenylindole
- BIC
- Brain iron content
- DAB
- 3-3-diaminobenzidine tetrahydrochloride
- Ctx
- Cerebral cortex
- Hip
- Hippocampus
- 3V
- third ventricle
- WT Y
- wild type Young
- WT A
- wild type Adult
- WT M-A
- wild type Middle-aged
- WT O
- wild type Old
- ALS
- Amyotrophic Lateral Sclerosis
- TJ
- Tight junction
- BVECs
- brain vascular endothelia cells
- TDT
- transfusion dependent thalassemia
- BMP6
- Bone Morphogenetic Protein 6
- TMPRSS6
- Transmembrane Serine Protease 6
