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Ph.D. Defence by Lisa Juul Routhe

Lisa Juul Routhe will defend her Ph.D. thesis on: "Neuroinflammation and iron handling in animal models with brain iron overload"

Time

03.05.2019 kl. 13.00 - 17.00

Description

See the invitation here.

Abstract

Iron is essential for living organisms, and tight regulation of iron homeostasis is vital since defective iron homeostasis can have harmful effects. Throughout life, the brain takes up iron from the periphery through the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. The turnover of iron is extremely low, which can explain why iron concentrations increase in the brain in healthy aging. In pathology, like hemorrhagic stroke and many neurodegenerative diseases, defective iron homeostasis can result in iron accumulation and consequently changes in the cellular distribution of iron and cell damage. Furthermore, an inflammatory reaction in the brain parenchyma is a common response in these diseases. The inflammatory process involves the activation of microglia and astrocytes and infiltration of circulating immune cells, which further perturbs iron homeostasis. Glia cells upregulate their iron up-take and increase numerous iron-related proteins, which include heme oxygenase-1 (HO-1) that releases free iron by degrading heme, and the iron storage protein, ferritin. Several iron-related proteins, such as lipocalin 2 (LCN2) and Zrt-, Irt-like protein 14 (ZIP14) are regu-lated by inflammatory stimuli in the periphery. LCN2 functions to limit available iron for bacteria and participates in iron homeostasis, while ZIP14 imports divalent metal ions in the liver, heart, and pan-creas. However, there is still lacking evidence of whether they are regulated during pathology in the brain. This dissertation focuses on iron handling in the brain in conditions with iron overload and neu-roinflammation. In order to study this, animal models of hemorrhagic stroke, i.e. intracerebral hemor-rhage (ICH) and intraventricular hemorrhage (IVH), and a model of chronic neurodegeneration were used. In Study I, the role of the choroid plexus in handling hemoglobin was studied using in vitro and in vivo models of IVH. The regulation of the transferrin receptor, ferritin, HO-1, LCN2 and lipocalin receptor, 24p3R was investigated after hemoglobin exposure. An experimental model of ICH was established by administrating arterial autologous whole blood into the striatum of rats. Characterization of the model includes investigation of iron content, ferritin, and HO-1 expression. Study II examined the modulation of ZIP14 expression in the model of ICH, whereas Study III investigated the regulation of ZIP14 in an experimental model of chronic neurodegeneration in the substantia nigra pars reticulata (SNpr). Since astrocytes were shown to modulate ZIP14 expression in both models, it was examined whether ZIP14 is regulated by blood derivatives, iron overload, and inflammation in cultures of astrocytes. Results from Study I demonstrate that the choroid plexus upregulates HO-1, acute-phase protein LCN2, and ferritin in response to hemoglobin exposure. While ferritin is probably upregulated as a cellular de-fense mechanism to store iron in a non-toxic form thereby limiting iron-induced cell damage, upregula-tion of LCN2 may be detrimental to the choroid plexus. Study II and III show that reactive astrocytes increase their expression of the iron importer, ZIP14, in animal models with increased brain iron and neuroinflammation. Furthermore, astrocyte cultures increase their Zip14 gene expression in response to hemoglobin, iron overload, and inflammation. Due to the dysregulation of iron homeostasis observed in ZIP14 knockdown astrocytes, we suggest that ZIP14 plays an essential role in astrocytic iron homeosta-sis in pathology. Additionally, ZIP14 could serve as a neuroprotective mechanism by limiting free extra-cellular iron and neuronal cell death. Together, these studies show that LCN2 and ZIP14 may play significant roles in handling iron in the choroid plexus and astrocytes, respectively, in pathological conditions.

Host

Department of Health Science and Technology, Aalborg University

Address

Fredrik Bajers Vej 7D2, room D2-106

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