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Role of inflammation and microglia in amyotrophic lateral sclerosis

Thesis

French

ID: <http://hdl.handle.net/20.500.11794/20796>
Disciplines

Abstract

amyotrophic lateral sclerosis (LA) is a fatal disease characterised by the degenerescence of motor neurons. The majority of SLA cases are sporadic (SLAs) and the rest are family cases (SLAf) being genetically inherited. A portion of SLAf cases is associated with mutations in the Cu/Zn dismutasis superoxide gene (SOD1). Microgliosis is a pathological characteristic observed in tissues in patients with nervous system diseases including ALS. Microgliosis and inflammatory response in the CNS may have beneficial or adverse effects. For example, microglial activation in the SLA pathology could promote neural survival but could also cause or exacerbate the degeneration of motoneurones. To determine the role of microglies and inflammatory mediators in the degeneration of motoneurones caused by mutations in SOD1, we used the 5001 mutant mice, SLA models. As a first step (Chapter 2), in order to determine the role of TNF-a cytokine in the SLA, we generated mice expressing mutants 5001 G37R or 5001 G93A in a context where TNF-expression has been removed (knock-out mouse). In a second approach (Chapter 3), by flow cytometry, we characterised microglial cell populations in the spinal cord of mutant transgenic mice 5001 G93A. In this study we have shown that the increase in the number of microglial cells in this murin model is largely attributable to the proliferation of microglial cells. Subsequently, we used CD11b-TK-30 transgenic mice, where proliferation microglies can be selectively eliminated, to determine the role of proliferation microglies in SLA caused by mutations in SOD1. In a last study, we tried to induce a neuroprotective phenotype to microglial cells through the administration of the macrophage colony stimulating factor (M-CSF) in transgenic mice 5001 G37R and in 5001 G37R chemic mice that have undergone wild bone marrow transplantation.

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