Physiopathological changes of ferritin mRNA density and distribution in hippocampal astrocytes in the mouse brain

• Published in: Journal of neurochemistry Vol. 164; no. 6; pp. 847 - 857
• Main Authors: Tortuyaux, Romain, Avila‐Gutierrez, Katia, Oudart, Marc, Mazaré, Noémie, Mailly, Philippe, Deschemin, Jean‐Christophe, Vaulont, Sophie, Escartin, Carole, Cohen‐Salmon, Martine
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2023; Wiley
• Subjects: Aging; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides; Animals; Astrocytes; Astrocytes - metabolism; Brain; Density; Ferritin; Ferritins - genetics; Ferritins - metabolism; FISH; Hemochromatosis; Hepcidin; Hepcidins; Hippocampus; Hippocampus - metabolism; Homeostasis; Iron; Iron - metabolism; Life Sciences; Localization; Mice; Mice, Knockout; Neurobiology; Neurodegenerative diseases; Neurons and Cognition; RNA, Messenger; Transcriptomics; Translation; FISH; ferritin; aging; astrocytes; hippocampus; hemochromatosis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15747

Astrocytes are thought to play a crucial role in brain iron homeostasis. How they accomplish this regulation in vivo is unclear. In a recent transcriptomic analysis, we showed that polysomal Ftl1 and Fth1 mRNAs, encoding the ferritin light (Ftl) and heavy (Fth) chains that assemble into ferritin, a critical complex for iron storage and reduction, are enriched in perisynaptic astrocytic processes as compared to astrocytic soma. These data suggested that ferritin translation plays a specific role at the perisynaptic astrocytic interface and is tighly regulated by local translation. Here, we used our recently described AstroDot 3D in situ methodology to study the density and localization of ferritin mRNAs in astrocytes in the hippocampus in three different contexts in which local or systemic iron overload has been documented: aging, the hepcidin knock‐out mouse model of hemochromatosis and the APP/PS1dE9 mouse model of Alzheimer's disease (AD). Our results showed that in wild type mice, Fth1 mRNA density was higher than Ftl1 and that both mRNAs were mostly distributed in astrocyte fine processes. Aging and absence of hepcidin caused an increased Fth1/Ftl1 ratio in astrocytes and in the case of aging, led to a redistribution of Fth1 mRNAs in astrocytic fine processes. In contrast, in AD mice, we observed a lower Fth1/Ftl1 ratio. Fth1 mRNAs became more somatic and Ftl1 mRNAs redistributed in large processes of astrocytes proximal to Amyloid beta (Aß) deposits. Hence, we propose that regulation of ferritin mRNA density and distribution in astrocytes contribute to iron homeostasis in physiology and pathophysiology. In this study, we used the AstroDot 3‐dimension in situ methodology to study the density and localization of Fth1 and Ftl1 mRNAs encoding ferritin in CA1 hippocampal astrocytes. We show that both mRNAs are mostly distributed in astrocyte fine processes. They redistribute differentially in aging, the hepcidin knock‐out mouse model of hemochromatosis and the APP/PS1dE9 mouse model of Alzheimer's disease which are three different contexts in which local or systemic iron overload has been documented. We propose that regulation of ferritin mRNA density and distribution in astrocytes contribute to iron homeostasis in physiology and pathophysiology.