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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.

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. [ABSTRACT FROM AUTHOR]

Motoneuron degeneration is the hallmark of amyotrophic lateral sclerosis (ALS). The cause and predisposing factors for sporadic ALS are still unknown. Exposure to a specific environmental risk factors in subjects with a susceptibility genotype may increase the risk of the disease. The role of physical activity and the use of anabolic steroids are still debated in epidemiological studies on patients and murine models of ALS. To assess at the cellular level the role (beneficial or detrimental) of physical exercise and the use of anabolic steroid, we here investigated, in SOD1(G93A) (mSOD1) mice and wild-type littermates, changes in the ventral horn after regular exercise, treatment with the anabolic androgenic steroid 19-nortestosterone (nandrolone), and their combination, compared with matched control sedentary mice. The experiments were pursued for several weeks until symptom onset in mSOD1 mice. Lumbar motoneurons, astrocytes and microglia were analyzed. In wild-type mice, cytological alterations of motoneurons were observed especially after nandrolone treatment. The following main findings were observed in treated mSOD1 mice versus untreated ones: i ) nandrolone treatment markedly enhanced motoneuron loss; this detrimental effect was reverted by the combination with exercise, resulting in increased motoneuron survival; ii ) astrocytic activation was most marked after nandrolone treatment when motoneuron damage was most severe; iii ) microglia activation was most marked after physical exercise when motoneuron damage was less severe. The results indicate a vulnerability of mSOD1 motoneurons to nandrolone treatment, a potential neuroprotective effect of physical exercise, and a modulation by glial cells in the ALS murine model in the examined paradigms. [ABSTRACT FROM AUTHOR]