**The Role of TNF-Alpha in ALS: New Hypotheses for Future Therapeutic Approaches**

Cristina Cereda1\*, Stella Gagliardi1\*,

Emanuela Cova1, Luca Diamanti2,3 and Mauro Ceroni2,3 *1Laboratory of Experimental Neurobiology, IRCCS, National Neurological Institute "C. Mondino", Pavia, 2General Neurology Department, IRCCS, National Neurological Institute "C. Mondino", Pavia, 3Department of Neurological Sciences, University of Pavia, Pavia, Italy* 

### **1. Introduction**

412 Amyotrophic Lateral Sclerosis

Worms, P. M. (2001). The epidemiology of motor neuron diseases: a review of recent studies.

Zhao, W., Beers, D. R., Henkel, J. S., Zhang, W., Urushitani, M., Julien, J. P. & Appel, S. H.

*Glia,* Vol.58, No.2, (January 2010), pp.231-243, ISSN 1098-1136.

0022-510X.

*Journal of the neurological sciences,* Vol.191, No.1-2, (October 2001), pp.3-9, ISSN

(2010). Extracellular mutant SOD1 induces microglial-mediated motoneuron injury.

The pathophysiological origins of neurodegenerative disorders are a complex combination of both environmental and genetic factors. However, in many of these disorders, processes such as inflammation and oxidative stress activate common and final pathways leading to toxicity and cellular death. High levels of oxidative damage within the brain and the activation of neuroinflammation factors are a prominent feature in patients with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS) and inherited ataxias (Halliwell, 2006; Lin & Beal, 2006). Regarding the immunological point of view, the brain was considered an immune privileged organ because it was isolated from the systemic circulation by protective bloodbrain barrier that controls the infiltration of pathogens, the transition of pro or anti inflammatory factors and peripheral blood cells (Itzhaki et al., 2004). Despite that, in recent years, the relationship between neuroinflammation and neurodegeneration has been described with particular attention to the lymphocytes activation and cytokines production (Appel, 2009; Tansey et al., 2007). Moreover, it is well known the implication of glial cells in the progression of neurodegeneration: they are involved in many types of damage, they migrate to the damaged cells and also they have a role in clearing the debris of the dead cells. Through such processes, microglia releases reactive oxygen species, proinflammatory cytokines, complement factors, and neurotoxic molecules, leading to further neuronal dysfunction and death (Heneka et al., 2011; Lasiene et al., 2011). In addition, the implication of the peripheral system and its participation in the cellular mechanisms that direct to neurodegeneration, as white blood cells, is well documented (Calvo et al., 2010; Ghezzi et al., 1998; Gowing et al., 2006).

Many data from autoptic spinal cord and blood examinations of the ALS patients, animal and cellular models support an immune system involvement in ALS pathogenesis. Since

<sup>\*</sup> These authors contributed equally to this work.

The Role of TNF-Alpha in ALS: New Hypotheses for Future Therapeutic Approaches 415

Innate immunity is naturally present and is not stimulated by antigens or mediated by antibodies. It is therefore non-specific and is executed by a variety of cells: granulocytes, as eosinophils and basophils, white blood cells as natural killer and mast cells. Instead, microglia belongs to the central nervous system and is involved in the local innate

Interactions between innate immune system, brain and neurodegenerative diseases are known (Ghezzi et al., 1998; Gowing et al., 2006) and it has been reported that mast cells, macrophages, dendritic cells, microglia, complement and cytokines participate in limiting

Innate system was found activated in central and in peripheral system of ALS patients

Several studies regarding peripheral innate immune system changes in sporadic ALS reveal that there are increased levels of circulating monocytes and macrophages (Harman et al., 1991; Hemnani et al, 1998). The presence of T cells, IgG, activated microglia, macrophages, and reactive astrocytes, as well as other indications of inflammation are found in ALS spinal

In ALS there is morphological and neurochemical evidence for the proliferation and activation of microglia in areas of significant motor neuron loss, as spinal cord (Henkel et al., 2004; Kawamata et al., 1992; Moisse et al., 2006). This activation may be a consequence of stressed neurons that induced proliferation and activation of microglial cells activating complement system and pro-cytokine response involved in neuronal death (Fig. 2). Motor neuron loss and immune system activation may increase neuron stress leading to increase of

As innate immunity, adaptive immunity has a role in ALS (Sta et al., 2011). Unlike innate immune responses, the adaptive responses are highly specific and they consist of antibodies, lymphocytes activation and cell mediated response. The cells of the adaptive immune system are B and T lymphocytes: B cells, which are derived from the bone marrow, become the cells that produce antibodies. T cells can cross-talk with neurons and microglia, and either damage or protect neurons from stressful stimuli (Alexaniu et al., 2001), also in spinal

T-helper cells have been observed in proximity of degenerating corticospinal tracts; T-helper and T-suppressor cells, with a variable number of macrophages, have been found in ventral

Infiltration of T cells compatible with adaptive response have been found in the areas of motor neuron destruction in the CNS but no correlation was found between clinical

immunity. Inflammation is one of the aspects of the innate immune response.

cord tissue (Henkel et al., 2004; Engelhardt et al., 1995; Troost et al., 1990).

**2.1 Innate immune system** 

the damage (Calvo et al., 2010).

neuroinflammation.

**2.2 Adaptive immune system** 

cord and brain (Chiu et al., 2008).

horns of the spinal cord (Troost et al., 1990).

(Chandels et al., 2001; Elliott et al., 2001; Sta et al., 2011).

Fig. 2. Hypothesis of activation of innate immunity in ALS.

1984 the presence of an autoimmunity component in ALS was proven when immunoglobulin depositories have been described in spinal cord (Donnenfeld et al., 1984). At present the implication of the neuronal and non-neuronal immunological cells and activation of the inflammatory processes have been extensively described in ALS (Engelhardt et al., 1995; Henkel et al., 2004; Troost et al., 1990).

Starting from literature data about implication of the innate and adaptive immunity in ALS, we would like to point out the role of the TNF alpha (TNF-) system and its interactions in ALS pathway with particular attention to SOD1 protein, the most important player in the ALS pathogenesis. We will focus this book section on TNF- cytokine because its involvement both in immunological pathways and in oxidative stress is known in ALS disease. Moreover we will try to define the immunological actors that exert a protective function and how they could be used in a possible therapy.
