Physiopathological changes of ferritinmRNAdensity and distribution in hippocampal astrocytes in the mouse brain

• DOI: 10.1111/jnc.15747
• Publication Date: 2022-12-23T14:44:25Z
• Authors: Romain Tortuyaux; Katia Avila‐Gutie...; Marc Oudart; Noémie Mazaré; Philippe Mailly; Jean‐Christophe D...; Sophie Vaulont; Carole Escartin; Martine Cohen‐Salmon
• Keywords: Mice, Knockout; 0303 health sciences; Amyloid beta-Peptides; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Iron; Hippocampus; Mice; 03 medical and health sciences; Hepcidins; Alzheimer Disease; Astrocytes; Ferritins; Animals; RNA, Messenger

AbstractAstrocytes 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 polysomalFtl1andFth1mRNAs, 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 describedAstroDot3D 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,Fth1mRNA density was higher thanFtl1and that both mRNAs were mostly distributed in astrocyte fine processes. Aging and absence of hepcidin caused an increasedFth1/Ftl1ratio in astrocytes and in the case of aging, led to a redistribution ofFth1mRNAs in astrocytic fine processes. In contrast, in AD mice, we observed a lowerFth1/Ftl1ratio.Fth1mRNAs became more somatic andFtl1mRNAs 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.image