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**18** 

*Italy* 

**The Role of TNF-Alpha in ALS: New Hypotheses** 

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

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

**1. Introduction** 

al., 1998; Gowing et al., 2006).

These authors contributed equally to this work.

 \*

**for Future Therapeutic Approaches** 

Emanuela Cova1, Luca Diamanti2,3 and Mauro Ceroni2,3

*3Department of Neurological Sciences, University of Pavia, Pavia,* 

Cristina Cereda1\*, Stella Gagliardi1\*,

*2General Neurology Department, IRCCS,* 

*1Laboratory of Experimental Neurobiology, IRCCS, National Neurological Institute "C. Mondino", Pavia,* 

*National Neurological Institute "C. Mondino", Pavia,* 

