Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase

Centre de Recherche du Centre Hospitalier Universitaire de Québec, Department of Psychiatry and Neuroscience of Laval University, Quebec, Pavillon CHUL, 2705 Boulevard Laurier, Quebec, Canada.
Experimental Neurology (Impact Factor: 4.7). 10/2009; 220(2):267-75. DOI: 10.1016/j.expneurol.2009.08.021
Source: PubMed


Macrophage colony stimulating factor (M-CSF) is a cytokine that regulates the survival, proliferation and maturation of microglial cells. Administration of M-CSF can promote neuronal survival in various models of central nervous system (CNS) injury. Here, in an attempt to induce a neuroprotective microglial cell phenotype and enhance motor neuron survival, mutant SOD1(G37R) transgenic mice were treated, weekly, with M-CSF starting at onset of disease. Unexpectedly, M-CSF accelerated disease progression in SOD1(G37R) mouse model of ALS. The shortened survival of M-CSF-treated animals was associated with diminished muscle innervation and enhanced adoption of a macrophage-like phenotype by microglial cells characterised by the upregulation of pro-inflammatory cytokines TNF-alpha and IL-1 beta and of the phagocytic marker CD68.

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Available from: Jean-Nicolas Audet, Oct 05, 2015
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    • "The generation of transgenic animals that carry mutated human genes associated with familial ALS, for instance superoxide dismutase (SOD1), tar DNA protein 43 (TDP- 43), fused in sarcoma, and valosin-containing protein genes, has allowed the identification of basic mechanisms underlying neurodegeneration in the disease (McGoldrick et al., 2013). In fact, distinct processes of motor neuron death that are related to toxic glial paracrine (Nagai et al., 2007; Gowing et al., 2009) and autocrine (Ringer et al., 2012) signaling mechanisms have been described using animal models. Furthermore, the early peripheral pathological events of neuromuscular junction loss and motor axon retraction, which may start long before symptom onset, have also been described in these animal models (Rocha et al., 2013; Venkova et al., 2014). "
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    • "Other alternative approaches have studied the impact of increasing the proliferative activity of microglia with recombinant CSF1. These studies also suggest a detrimental role for microglia in the pathophysiology of ALS (Gowing and others 2009), although these experiments also affected the contribution from CSF1-responsive "
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