The Dual Role of Microglia in ALS: Mechanisms and Therapeutic Approaches - PubMed (original) (raw)

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The Dual Role of Microglia in ALS: Mechanisms and Therapeutic Approaches

Maria Concetta Geloso et al. Front Aging Neurosci. 2017.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a non-cell autonomous motor neuron loss. While it is generally believed that the disease onset takes place inside motor neurons, different cell types mediating neuroinflammatory processes are considered deeply involved in the progression of the disease. On these grounds, many treatments have been tested on ALS animals with the aim of inhibiting or reducing the pro-inflammatory action of microglia and astrocytes and counteract the progression of the disease. Unfortunately, these anti-inflammatory therapies have been only modestly successful. The non-univocal role played by microglia during stress and injuries might explain this failure. Indeed, it is now well recognized that, during ALS, microglia displays different phenotypes, from surveillant in early stages, to activated states, M1 and M2, characterized by the expression of respectively harmful and protective genes in later phases of the disease. Consistently, the inhibition of microglial function seems to be a valid strategy only if the different stages of microglia polarization are taken into account, interfering with the reactivity of microglia specifically targeting only the harmful pathways and/or potentiating the trophic ones. In this review article, we will analyze the features and timing of microglia activation in the light of M1/M2 phenotypes in the main mice models of ALS. Moreover, we will also revise the results obtained by different anti-inflammatory therapies aimed to unbalance the M1/M2 ratio, shifting it towards a protective outcome.

Keywords: M1/M2 microglia; amyotrophic lateral sclerosis; anti-inflammatory drugs; genetic modifiers; mutant SOD1 mice; neuroinflammation.

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Figures

Figure 1

Figure 1

M1/M2 microglia polarization during amyotrophic lateral sclerosis (ALS)-induced motor neuron degeneration. During ALS progression activated microglia represent a continuum between the neuroprotective M2 phenotype, which promotes tissue repair and supports neuron survival by releasing neuroprotective factors, vs. the toxic M1, which produces cytokines increasing inflammation and further supporting M1 polarization, thus contributing to neuronal death. Therapeutic approaches targeting microglia polarization and resulting in induction of the M2 phenotype are promising strategies to ameliorate local neurodegeneration and improve the clinical outcome of the disease (see Table 1 for details).

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References

    1. Acsadi G., Anguelov R. A., Yang H., Toth G., Thomas R., Jani A., et al. . (2002). Increased survival and function of SOD1 mice after glial cell-derived neurotrophic factor gene therapy. Hum. Gene Ther. 13, 1047–1059. 10.1089/104303402753812458 - DOI - PubMed
    1. Ahmad L., Zhang S.-Y., Casanova J.-L., Sancho-Shimizu V. (2016). Human TBK1: a gatekeeper of neuroinflammation. Trends Mol. Med. 22, 511–527. 10.1016/j.molmed.2016.04.006 - DOI - PMC - PubMed
    1. Al-Chalabi A., Hardiman O. (2013). The epidemiology of ALS: a conspiracy of genes, environment and time. Nat. Rev. Neurol. 9, 617–628. 10.1038/nrneurol.2013.203 - DOI - PubMed
    1. Al-Chalabi A., Van Den Berg L. H., Veldink J. (2017). Gene discovery in amyotrophic lateral sclerosis: implications for clinical management. Nat. Rev. Neurol. 13, 96–104. 10.1038/nrneurol.2016.182 - DOI - PubMed
    1. Alexianu M. E., Kozovska M., Appel S. H. (2001). Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57, 1282–1289. 10.1212/wnl.57.7.1282 - DOI - PubMed

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