Effects of Macrophage Migration Inhibitory Factors’ (MIF) inhibition on chronic neuroinflammation

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Considering the aging population, AD will be one of the challenging problems of the public health in the near future. Current medication used for AD can only alleviate the symptoms temporar...

Full description

Saved in:
Bibliographic Details
Main Author: Nasiri, Elham
Contributors: Bacher, Michael (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:English
Published: Philipps-Universität Marburg 2016
Subjects:
Online Access:PDF Full Text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Considering the aging population, AD will be one of the challenging problems of the public health in the near future. Current medication used for AD can only alleviate the symptoms temporarily; therefore it is imperative to identify new therapeutic targets to prevent the progression of the disease. Being one of the early key events in early AD pathology, chronic inflammation precedes the cognitive decline and an increasing interest has been focused on identifying potential targets within inflammatory cascades. Macrophage Migration Inhibitory Factor (MIF) is a multi-potent proinflammatory cytokine, which promotes production of other proinflammtory mediators. MIF is synthesized by several cell types in the brain such as microglia, astrocytes and hippocampal neurons, and is secreted in early asymptomatic stage of the disease, which might contribute to the persistent activation of glial cells and perpetuating neuroinflammatory responses leading to neurodegeneration. In this project we hypothesized that inhibition of MIF can attenuate the inflammatory milieu in the brain and improve the cognitive deficits as a result of chronic cytokine production. We used Intracerebroventricular Streptozotocin Injections (STZ-ICV) to test our hypothesis. In in vitro experiments, ISO-1 was used to inhibit the MIF molecule in primary astrocyte, neuron and microglia treated with proper concentrations of STZ molecule as stimulus. The cytokine response was documented in protein and mRNA level. The collected in vitro data suggests that MIF inhibition can alleviate inflammation by down-regulating production of proinflammtory cytokines (such as IL-6 and IL-12p40). In vitro experiments were followed up by in vivo behavioral assessment of cognitive deficits and cytokine production in streptozotocin induced model of neurodegeneration. For this purpose, MIF-KO and wild type mice were intracerebroventricularly injected with streptozotocin (STZ-ICV) or vehicle (Veh-ICV). We confirmed that by triggering an ongoing and chronic immune response, STZ interferes with learning via disrupting the spatial learning in C57BL/6 mice. We observed significant relationships between cognitive improvement (in terms of contextual memory) and MIF inhibition in STZ-ICV model for neuroinflammation. The inhibition of MIF (by novel Intraperitoneal (IP) application of ISO-1), tended to improve the spatial learning and memory in the context of clockmaze and fear conditioning in wild type animal. Similar trend as in vitro has been observed in down regulation of cytokines (IL-6 and IL-12p40) as a result of MIF inhibition. In contrast to wild type STZ-ICV, we observed no significant upregulation in inflammatory mediator or glial cell markers in mRNA levels of MIF-KO animals. In conclusion, the results from my thesis confirms the role of MIF as an upstream cytokine in regulating secretion of other inflammatory mediators and shows the potential of this molecule as a therapeutic target to attenuate cytokine induced cognitive deficits.
Physical Description:165 Pages
DOI:https://doi.org/10.17192/z2017.0151