Effects of conditional knockout ceruloplasmin in astrocytes on brain iron metabolism of mice

LI Hai-yan LI Zhong-da HE Li-juan

Acta Anatomica Sinica ›› 2024, Vol. 55 ›› Issue (4) : 475-481.

PDF(5883 KB)
Welcome to visit Acta Anatomica Sinica! Today is Chinese
PDF(5883 KB)
Acta Anatomica Sinica ›› 2024, Vol. 55 ›› Issue (4) : 475-481. DOI: 10.16098/j.issn.0529-1356.2024.04.014
Research Articles

Effects of conditional knockout ceruloplasmin in astrocytes on brain iron metabolism of mice

  • LI Hai-yan1,2* LI Zhong-da2 HE Li-juan2
Author information +
History +

Abstract

Objective To explore the mechanism of ceruloplasmin(CP) in brain iron metabolism. Methods  We obtained glial fibrillary acidic protein(GFAP)-cre-mediated ceruloplasmin knockout mice (CPGFAP cKO mice) by crossing CPflox/flox mice with transgenic GFAP-cre mice. Eighty-eight male mice aged 6 months were divided into four groups, WT, GFAP-cre, CPflox/flox and CPGFAP cKO. To observe whether astrocytic CP gene knockout specifically through genotype identification and immunofluorescent staining, and Western blotting method. The learning and memory function was detected by Morris water maze, brain iron levels in the cortex and hippocampus of mice were measured by inductively coupled plas mamass spectrometry(ICP-MS) and μ-probe X-ray fluorescence(μ-XRF), and iron contents in serum and liver were detected by iron kit. Results The mice of conditional knockout ceruloplasmin in astrocytes were obtained successfully by genotype identification, immunofluorescent staining and Western blotting method. The learning and memory ability was reduced in the water maze experiment, and iron contents decreased in the cortex and hippocampal regions of 6-month-old CPGFAP cKO group. While the level of serum iron and liver iron in the four groups did not change significantly. Conclusion The decline of learning and memory ability of mice with astrocytic CP gene knockout specifically is closely related to the decrease in brain iron. The main function of CP may be to help brain cells to absorb iron.

Key words

Ceruloplasmin / Astrocyte / Iron / Cognition / Western blotting / Mouse

Cite this article

Download Citations
LI Hai-yan LI Zhong-da HE Li-juan. Effects of conditional knockout ceruloplasmin in astrocytes on brain iron metabolism of mice[J]. Acta Anatomica Sinica. 2024, 55(4): 475-481 https://doi.org/10.16098/j.issn.0529-1356.2024.04.014

References

[1]Yu P, Duan XL, Zhang M, et al. Effect of high iron on the expressionof divalent metal transpter 1 in the cerebral cortex of rats[J]. Acta Anatomica Sinica, 2011, 42(4): 435-440. (in Chinese) 
于鹏,段相林,张明,等. 高铁对大鼠大脑皮层二价金属转运蛋白1表达的影响[J].解剖学报,2011,42(4):435-440. 
[2]Hadzhieva M, Kirches E, Mawrin C. Review: iron metabolism and the role of iron in neurodegenerative disorders[J]. Neuropathol Appl Neurobiol, 2014, 40(3): 240-257.
[3]Lozoff B, Beard J, Connor J, et al. Long-lasting neural and behavioral effects of iron deficiency in infancy[J]. Nutr Rev, 2006, 64(5 Pt 2): S34-S43, S72-91.
[4]Yan HF, Zou T, Tuo QZ, et al. Ferroptosis: mechanisms and links with diseases[J]. Signal Transduct Target Ther, 2021, 6(1):49.
[5]Muckenthaler MU, Rivella S, Hentze MW, et al. A red carpet for iron metabolism[J]. Cell, 2017, 168(3):344-361.
[6]Qian ZM, Ke Y. Rethinking the role of ceruloplasmin in brain iron metabolism[J]. Brain Res Rev, 2001, 35(3): 287-294.
[7]Li ZD, Li H, Kang S, et al. The divergent effects of astrocyte ceruloplasmin on learning and memory function in young and old mice[J]. Cell Death Dis, 2022, 13(11):1006.
[8]Osaki S, Johnson DA, Frieden E. The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum[J]. J Biol Chem, 1966, 241(12): 2746-2751.
[9]Miyajima H. Aceruloplasminemia[J]. Neuropathology, 2015, 35(1): 83-90.
[10]Patel BN, Dunn RJ, Jeong SY, et al. Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury[J]. J Neurosci, 2002, 22(15): 6578-6586. 
[11]Santiago González DA, Cheli VT, Rosenblum SL, et al. Ceruloplasmin deletion in myelinating glial cells induces myelin disruption and oxidative stress in the central and peripheral nervous systems[J]. Redox Biol, 2021, 46: 102118.
[12]Jeong SY, David S. Age-related changes in iron homeostasis and cell death in the cerebellum of ceruloplasmin-deficient mice[J]. J Neurosci, 2006, 26(38): 9810-9819.
[13]Texel SJ, Camandola S, Ladenheim B, et al. Ceruloplasmin deficiency results in an anxiety phenotype involving deficits in hippocampal iron, serotonin and BDNF[J]. J Neurochem, 2012, 120(1): 125-134.
[14]Cheli VT, Sekhar M, Santiago González DA, et al. The expression of ceruloplasmin in astrocytes is essential for postnatal myelination and myelin maintenance in the adult brain[J]. Glia, 2023,71(10): 2323-2342.
[15]Cheli VT, Correale J, Paez PM, et al. Iron metabolism in oligodendrocytes and astrocytes, implications for myelination and remyelination[J].ASN Neuro, 2020, 12: 1759091420962681.
[16]Connor JR, Menzies SL. Relationship of iron to oligodendrocytes and myelination[J]. Glia, 1996, 17(2): 83-93.
[17]Badaracco ME, Ortiz EH, Soto EF, et al. Effect of transferrin on hypomyelination induced by iron deficiency[J]. J Neurosci Res, 2008, 86(12): 2663-2673.
[18]Rosato-Siri MV, Marziali L, Guitart ME, et al. Iron availability compromises not only oligodendrocytes but also astrocytes and microglial cells[J]. Mol Neurobiol, 2018, 55(2): 1068-1081.
[19]Khattar N, Triebswetter C, Kiely M, et al. Investigation of the association between cerebral iron content and myelin content in normative aging using quantitative magnetic resonance neuroimaging[J]. Neuroimage, 2021, 239: 118267.
[20]Monko TR, Tripp EH, Burr SE, et al. Cellular iron deficiency disrupts thyroid hormone regulated gene expression in developing hippocampal neurons[J]. J Nutr, 2024, 154(1):49-59.

PDF(5883 KB)

Accesses

Citation

Detail

Sections
Recommended

/