4 research outputs found
Impaired Iron Homeostasis and Haematopoiesis Impacts Inflammation in the Ageing Process in Down Syndrome Dementia.
Down syndrome (DS) subjects are more likely to develop the clinical features of Alzheimer's disease (AD) very early in the disease process due to the additional impact of neuroinflammation and because of activation of innate immunity. Many factors involved in the neuropathology of AD in DS, including epigenetic factors, innate immunity and impaired haematopoiesis, contribute significantly towards the pathophysiology and the enhanced ageing processes seen in DS and as a consequence of the triplication of genes RUNX1, S100β and OLIG2, together with the influence of proteins that collectively protect from cellular defects and inflammation, which include hepcidin, ferritin, IL-6 and TREM2. This study is aimed at determining whether genetic variants and inflammatory proteins are involved in haematopoiesis and cellular processes in DS compared with age-matched control participants, particularly with respect to neuroinflammation and accelerated ageing. Serum protein levels from DS, AD and control participants were measured by enzyme-linked immunosorbent assay (ELISA). Blood smears and post-mortem brain samples from AD and DS subjects were analysed by immunohistochemistry. RUNX1 mRNA expression was analysed by RT-PCR and in situ hybridisation in mouse tissues. Our results suggest that hepcidin, S100β and TREM2 play a critical role in survival and proliferation of glial cells through a common shared pathway. Blood smear analysis showed the presence of RUNX1 in megakaryocytes and platelets, implying participation in myeloid cell development. In contrast, hepcidin was expressed in erythrocytes and in platelets, suggesting a means of possible entry into the brain parenchyma via the choroid plexus (CP). The gene product of RUNX1 and hepcidin both play a critical role in haematopoiesis in DS. We propose that soluble TREM2, S100β and hepcidin can migrate from the periphery via the CP, modulate the blood-brain immune axis in DS and could form an important and hitherto neglected avenue for possible therapeutic interventions to reduce plaque formation
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Hepcidin Increases Cytokines in Alzheimer's Disease and Down's Syndrome Dementia: Implication of Impaired Iron Homeostasis in Neuroinflammation.
The liver-derived hormone hepcidin, a member of the defensin family of antimicrobial peptides, plays an important role in host defense and innate immunity due to its broad antibacterial and antiviral properties. Ferritin, an iron storage protein is often associated with iron deficiency, hypoferritinemia, hypoxia, and immune complications, which are all significant concerns for systemic infection in Alzheimer's disease (AD) and Down's syndrome (DS) dementia. Serum and post-mortem brain samples were collected from AD, DS and age-matched control subjects. Serum samples were analyzed with ELISA for ferritin, hepcidin and IL-6. Additionally, post-mortem brain sections were assessed by immunohistochemistry for iron-related and inflammatory proteins. A significant increase in serum hepcidin levels was found in DS, compared to controls and AD subjects (p < 0.0001). Hepcidin protein was visible in the epithelial cells of choroid plexus, meningeal macrophages and in the astrocytes close to the endothelium of blood vessels. Hepcidin co-localized with IL-6, indicating its anti-inflammatory properties. We found significant correlation between hypoferritinemia and elevated levels of serum hepcidin in AD and DS. Hepcidin can be transported via macrophages and the majority of the vesicular hepcidin enters the brain via a compromised blood brain barrier (BBB). Our findings provide further insight into the molecular implications of the altered iron metabolism in acute inflammation, and can aid towards the development of preventive strategies and novel treatments in the fight against neuroinflammation
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Hepcidin Increases Cytokines in Alzheimer's Disease and Down's Syndrome Dementia: Implication of Impaired Iron Homeostasis in Neuroinflammation.
The liver-derived hormone hepcidin, a member of the defensin family of antimicrobial peptides, plays an important role in host defense and innate immunity due to its broad antibacterial and antiviral properties. Ferritin, an iron storage protein is often associated with iron deficiency, hypoferritinemia, hypoxia, and immune complications, which are all significant concerns for systemic infection in Alzheimer's disease (AD) and Down's syndrome (DS) dementia. Serum and post-mortem brain samples were collected from AD, DS and age-matched control subjects. Serum samples were analyzed with ELISA for ferritin, hepcidin and IL-6. Additionally, post-mortem brain sections were assessed by immunohistochemistry for iron-related and inflammatory proteins. A significant increase in serum hepcidin levels was found in DS, compared to controls and AD subjects (p < 0.0001). Hepcidin protein was visible in the epithelial cells of choroid plexus, meningeal macrophages and in the astrocytes close to the endothelium of blood vessels. Hepcidin co-localized with IL-6, indicating its anti-inflammatory properties. We found significant correlation between hypoferritinemia and elevated levels of serum hepcidin in AD and DS. Hepcidin can be transported via macrophages and the majority of the vesicular hepcidin enters the brain via a compromised blood brain barrier (BBB). Our findings provide further insight into the molecular implications of the altered iron metabolism in acute inflammation, and can aid towards the development of preventive strategies and novel treatments in the fight against neuroinflammation
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Investigation of the ABI3 protein in microglia and its association with Alzheimer’s disease in TgCRND8 mouse model
Recent genome wide-association studies (GWAS) have identified several disease-related genetic variants among Alzheimer’s disease (AD) patients. A cluster of these genes, including TREM2, PLCG2 and ABI3, are highly expressed in microglia and their exact function in these cells is poorly understood. Since microglial dysfunction is thought to play an important role in AD pathogenesis, this thesis was aimed at analysing the expression and
cellular function of ABI3 in microglia within the context of AD pathology in the CRND8 transgenic mouse model.
Initially, commercial ABI3 antibodies were tested for their specificity in detecting endogenous ABI3 protein, using ABI3 knock-out (KO) mice as the negative control. These studies showed a punctate-like ABI3 expression across the cytoplasm in microglia. The following in vitro studies then focused on ABI3 cellular localization and showed limited co-localization
between ABI3 and filamentous actin in rat microglia. On the other hand, ABI3 was localized to the cellular regions with lower F-actin expression.
The functional role of ABI3 in microglia was studied by performing migration and phagocytosis assays in microglia. A significant increase in migration was seen after knocking down ABI3 in BV2 cells and similar results were observed in ABI3 KO primary microglia.
The consequences of ABI3 KO could also be seen in several aspects of amyloid-beta plaques properties since the number of the plaques as well as average plaque size were significantly lower in ABI3 KO x TgCRND8 mice. ABI3 KO microglia also showed significant changes in cell morphology and the expression levels of several actin cytoskeleton components.
Furthermore, ABI3 immunoreactivity in microglia was significantly higher in TgCRND8 mouse brains compared to age-matched controls; especially in the microglia surrounding the amyloid-beta plaques.
Finally, the consequences of ABI3 S209F mutation were investigated in transfected U2OS cells, purified ABI3 proteins and in S212F microglia by Western blotting, immunoprecipitation and immunofluorescence. Significant changes in ABI3 cellular expression pattern and posttranslational modifications, i.e., phosphorylation, were observed following S209F/S212F
mutation in ABI3.
The findings of this thesis highlight the ABI3 expression pattern in microglia, the significant changes in its expression during AD pathogenesis and the possible role of ABI3 in regulating microglial functions. These results will provide an insight into underlying mechanisms in which, ABI3 mutation may increase the risk of developing LOAD by altering microglial functions