Microglia as Potential Contributors to Motor Neuron Injury in Amyotrophic Lateral Sclerosis SIRANUSH A. SARGSYAN, PETER N. MONK, AND PAMELA J. SHAW * Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, United Kingdom KEY WORDS neuroinflammation; cytokines; motor neuron; microglia ABSTRACT The central nervous system (CNS) is equipped with a variety of cell types, all of which are assigned particular roles during the development, maintenance, function and repair of neural tissue. One glial cell type, microglia, deserves particular attention, as its role in the healthy or injured CNS is incom- pletely understood. Evidence exists for both regenerative and degenerative functions of these glial cells during neuro- nal injury. This review integrates the current knowledge of the role of microglia in an adult-onset neurodegenerative disease, amyotrophic lateral sclerosis (ALS), and pays parti- cular attention to the possible mechanisms of initiation and propagation of neuronal damage during disease onset and progression. Microglial cell properties, behavior and de- tected inflammatory reactions during the course of the dis- ease are described. The neuroinflammatory changes that occur in a mouse model of ALS are summarized. The under- standing of microglial function in the healthy and injured CNS could offer better diagnostic as well as therapeutic approaches for prevention, retardation, or repair of neural tissue degeneration. V V C 2005 Wiley-Liss, Inc. INTRODUCTION Amyotrophic lateral sclerosis (ALS), sometimes referred to as motor neuron disease (MND), is one of the most common adult-onset neurodegenerative diseases. Loss of motor neurons results in neuromuscular failure and death, usually from compromised respiratory func- tion, over a time course of approximately 2–3 years. ALS is a familial disease in 5–10% of cases and most insights into disease pathogenesis have come from the study of the effects of Cu/Zn superoxide dismutase-1 (SOD1) mutations, which account for 20% of familial cases (Andersen, 2003; Rosen et al., 1993). SOD1 is a ubiquitously distributed superoxide radical scavenging enzyme, with a major role in anti-oxidant defense. SOD1 mutations appear to cause motor neuron injury through a toxic gain of function that may include pro- tein aggregation, mitochondrial dysfunction, and aber- rant intracellular free radical handling (Gurney et al., 1996; Bruijn et al., 2004). The susceptibility of motor neurons to glutamatergic toxicity mediated by a-amino- 3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors may be an important determinant of selective vulnerability to neurodegeneration (Van Den Bosch et al., 2000; Heath and Shaw, 2002). However, despite a decade of research, the precise molecular mechanisms of motor neuron injury in the presence of mutant SOD1 remain incompletely understood. The involvement of non-neuronal cells in the pathology of neurodegenerative diseases, such as Alzheimer’s dis- ease, prion disease, or human immunodeficiency virus (HIV)-associated neurodegeneration, has been described (Eikelenboom et al., 2002; Garden, 2002; Rogers et al., 2002). Recently, there has been interest in the possibility that glial cells in the vicinity of degenerating motor neu- rons, mostly activated microglia and astrocytes, may con- tribute to the propagation of the disease process in ALS. Abundant gliosis is readily discernible in pathologically affected areas of the CNS, both in human ALS patients and in mouse models of disease (Kawamata et al., 1992; Hall et al., 1998). Biochemical evidence and gene expres- sion profiling have indicated that inflammatory cascades are activated before and during the process of motor neu- ron degeneration (Elliott, 2001; Yoshihara et al., 2002). Several studies in genetically engineered mouse models (transgenic mice carrying the human mutant SOD1 (hmSOD1) gene) have argued that expression of mutant SOD1 in neurons alone is insufficient to cause ALS and that participation of non-neuronal cells may be required (Gong et al., 2000; Pramatarova et al., 2001; Lino et al., 2002; Clement et al., 2003). Thus, mutant SOD1 may cause neurotoxicity indirectly by perturbing the function of non-neuronal cells including microglia. Microglia play a critical role as resident immunocompe- tent and phagocytic cells within the CNS. Activation is associated with increased production of potentially cyto- toxic molecules, including reactive oxygen species (ROS), nitric oxide (NO), proteases and pro-inflammatory cyto- kines, such as interleukin-1b (IL)-1b), tumor necrosis fac- tor-a (TNF-a), and IL-6, together with induction of phago- cytosis (Streit et al., 1999). Given these properties, there is little doubt that activated microglia can inflict signifi- cant damage on neighboring cells. However, their role is complex, and microglia can be neuroprotective as well as Grant sponsor: Wellcome Trust. *Correspondence to: Pamela J. Shaw, Academic Neurology Unit, E-Floor Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK. E-mail: pamela.shaw@sheffield.ac.uk Received 21 November 2004; Accepted 21 January 2005 DOI 10.1002/glia.20210 Published online 21 April 2005 in Wiley InterScience (www.interscience. wiley.com). V V C 2005 Wiley-Liss, Inc. GLIA 51:241–253 (2005)