Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motoneuron death. Mutations in the gene for superoxide dismutase 1 (SOD1) cause a familial form of ALS and have been used to develop transgenic mice which overexpress human mutant SOD1 (mSOD) and these mice exhibit a motoneuron disease which is pathologically and phenotypically similar to ALS. Neuroinflammation is a pathological hallmark of many neurodegenerative diseases including ALS and is typified by the activation and proliferation of microglia and the infiltration of T cells into the brain and spinal cord. Although the neuroinflammatory response has been considered a consequence of neuronal dysfunction and death, evidence indicates that manipulation of this response can alter disease progression. Previously viewed as deleterious to neuronal survival, recent reports suggest a trophic role for activated microglia in the mSOD mouse during the early stages of disease that is dependent on instructive signals from infiltrating T cells. However, at advanced stages of disease, activated microglia acquire increased neurotoxic potential, warranting further investigation into factors capable of skewing microglial activation towards a neurotrophic phenotype as a means of therapeutic intervention in ALS. 1. Introduction Neuroinflammation is a pathological hallmark of many neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). It is characterized by the activation and proliferation of microglia (microgliosis) and the accumulation of infiltrating T lymphocytes at sites of neurodegeneration. Although often considered a consequence to neuronal injury and degeneration, the neuroinflammatory response can have protective or deleterious effects on neuronal survival. These disparate effects are elicited by the heterogeneous activation programs of microglia, which in turn are dictated by their surrounding microenvironment and by infiltrating T cells. 2. Amyotrophic Lateral Sclerosis and the mSOD Mouse Model Typically diagnosed during the fifth decade of life, amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motoneurons in the brainstem and spinal cord and loss of descending motor tracts. Clinical manifestations of ALS include muscle weakness, spasticity, muscle atrophy, and advancing paralysis that culminates in respiratory failure, the usual cause of death in affected patients. ALS is a disease primarily of sporadic etiology with a
References
[1]
M. J. Strong, S. Kesavapany, and H. C. Pant, “The pathobiology of amyotrophic lateral sclerosis: a proteinopathy?” Journal of Neuropathology and Experimental Neurology, vol. 64, no. 8, pp. 649–664, 2005.
[2]
M. Neumann, D. M. Sampathu, L. K. Kwong et al., “Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis,” Science, vol. 314, no. 5796, pp. 130–133, 2006.
[3]
P. A. Dion, H. Daoud, and G. A. Rouleau, “Genetics of motor neuron disorders: new insights into pathogenic mechanisms,” Nature Reviews Genetics, vol. 10, no. 11, pp. 769–782, 2009.
[4]
M. E. Gurney, H. Pu, A. Y. Chiu et al., “Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation,” Science, vol. 264, no. 5166, pp. 1772–1775, 1994.
[5]
X. Shan, D. Vocadlo, and C. Krieger, “Mislocalization of TDP-43 in the G93A mutant SOD1 transgenic mouse model of ALS,” Neuroscience Letters, vol. 458, no. 2, pp. 70–74, 2009.
[6]
A. G. Reaume, J. L. Elliott, E. K. Hoffman et al., “Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury,” Nature Genetics, vol. 13, no. 1, pp. 43–47, 1996.
[7]
H. Ilieva, M. Polymenidou, and D. W. Cleveland, “Non-cell autonomous toxicity in neurodegenerative disorders: aLS and beyond,” Journal of Cell Biology, vol. 187, no. 6, pp. 761–772, 2009.
[8]
D. Jaarsma, E. Teuling, E. D. Haasdijk, C. I. De Zeeuw, and C. C. Hoogenraad, “Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice,” Journal of Neuroscience, vol. 28, no. 9, pp. 2075–2088, 2008.
[9]
S. Boillée, C. Vande Velde, and D. Cleveland, “ALS: a disease of motor neurons and their nonneuronal neighbors,” Neuron, vol. 52, no. 1, pp. 39–59, 2006.
[10]
D. R. Beers, J. S. Henkel, Q. Xiao et al., “Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 43, pp. 16021–16026, 2006.
[11]
A. C. Lepore, B. Rauck, C. Dejea et al., “Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease,” Nature Neuroscience, vol. 11, no. 11, pp. 1294–1301, 2008.
[12]
S. H. Appel, W. Zhao, D. R. Beers, and J. S. Henkel, “The microglial-motoneuron dialogue in ALS,” Acta Myologica, vol. 30, no. 1, pp. 4–8, 2011.
[13]
A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Neuroscience: resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo,” Science, vol. 308, no. 5726, pp. 1314–1318, 2005.
[14]
M. E. Lull and M. L. Block, “Microglial activation and chronic neurodegeneration,” Neurotherapeutics, vol. 7, no. 4, pp. 354–365, 2010.
[15]
G. W. Kreutzberg, “Microglia: a sensor for pathological events in the CNS,” Trends in Neurosciences, vol. 19, no. 8, pp. 312–318, 1996.
[16]
W. Zhao, W. Xie, W. Le et al., “Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism,” Journal of Neuropathology and Experimental Neurology, vol. 63, no. 9, pp. 964–977, 2004.
[17]
S. H. Appel, D. R. Beers, and J. S. Henkel, “T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening?” Trends in Immunology, vol. 31, no. 1, pp. 7–17, 2010.
[18]
R. H. Hoek, S. R. Ruuls, C. A. Murphy et al., “Down-regulation of the macrophage lineage through interaction with OX2 (CD200),” Science, vol. 290, no. 5497, pp. 1768–1771, 2000.
[19]
A. E. Cardona, E. P. Pioro, M. E. Sasse et al., “Control of microglial neurotoxicity by the fractalkine receptor,” Nature Neuroscience, vol. 9, no. 7, pp. 917–924, 2006.
[20]
N. Melzer, S. G. Meuth, and H. Wiendl, “CD8+ T cells and neuronal damage: direct and collateral mechanisms of cytotoxicity and impaired electrical excitability,” The FASEB Journal, vol. 23, no. 11, pp. 3659–3673, 2009.
[21]
R. S. Negrin, “Immunobiology of transplantation,” in Hematopoietic Stem Cell Transplanation, R. .J Soiffer, Ed., pp. 39–53, Humana Press, Boston, Mass, USA, 2008.
[22]
J. Kipnis and M. Schwartz, “Controlled autoimmunity in CNS maintenance and repair: naturally occurring CD4+CD25+ regulatory T-cells at the crossroads of health and disease,” NeuroMolecular Medicine, vol. 7, no. 3, pp. 197–206, 2005.
[23]
X. Huang, A. D. Reynolds, R. L. Mosley, and H. E. Gendelman, “CD4+ T cells in the pathobiology of neurodegenerative disorders,” Journal of Neuroimmunology, vol. 211, no. 1-2, pp. 3–15, 2009.
[24]
T. Holm？y, “T cells in amyotrophic lateral sclerosis,” European Journal of Neurology, vol. 15, no. 4, pp. 360–366, 2008.
[25]
E. Vivier and B. Malissen, “Innate and adaptive immunity: specificities and signaling hierarchies revisited,” Nature Immunology, vol. 6, no. 1, pp. 17–21, 2005.
[26]
B. Engelhardt and R. M. Ransohoff, “The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms,” Trends in Immunology, vol. 26, no. 9, pp. 485–495, 2005.
[27]
H. Neumann, I. M. Medana, J. Bauer, and H. Lassmann, “Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases,” Trends in Neurosciences, vol. 25, no. 6, pp. 313–319, 2002.
[28]
E. J. McMahon, S. L. Bailey, and S. D. Miller, “CNS dendritic cells: critical participants in CNS inflammation?” Neurochemistry International, vol. 49, no. 2, pp. 195–203, 2006.
[29]
J. Gehrmann, Y. Matsumoto, and G. W. Kreutzberg, “Microglia: intrinsic immuneffector cell of the brain,” Brain Research Reviews, vol. 20, no. 3, pp. 269–287, 1995.
[30]
I. Bechmann, G. Mor, J. Nilsen, M. Eliza, R. Nitsch, and F. Naftolin, “FasL (CD95L, Apo1L) is expressed in the normal rat and human brain: evidence for the existence of an immunological brain barrier,” Glia, vol. 27, no. 1, pp. 62–74, 1999.
[31]
T. Magnus, B. Schreiner, T. Korn et al., “Microglial expression of the B7 family member B7 homolog 1 confers strong immune inhibition: Implications for immune responses and autoimmunity in the CNS,” Journal of Neuroscience, vol. 25, no. 10, pp. 2537–2546, 2005.
[32]
D. Troost, J. J. Van den Oord, and J. M. B. Vianney de Jong, “Immunohistochemical characterization of the inflammatory infiltrate in amyotrophic lateral sclerosis,” Neuropathology and Applied Neurobiology, vol. 16, no. 5, pp. 401–410, 1990.
[33]
J. I. Engelhardt, J. Tajti, and S. H. Appel, “Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis,” Archives of Neurology, vol. 50, no. 1, pp. 30–36, 1993.
[34]
T. Kawamata, H. Akiyama, T. Yamada, and P. L. McGeer, “Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue,” American Journal of Pathology, vol. 140, no. 3, pp. 691–707, 1992.
[35]
M. R. Turner, A. Cagnin, F. E. Turkheimer et al., “Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study,” Neurobiology of Disease, vol. 15, no. 3, pp. 601–609, 2004.
[36]
R. Zhang, R. Gascon, R. G. Miller et al., “MCP-1 chemokine receptor CCR2 is decreased on circulating monocytes in sporadic amyotrophic lateral sclerosis (sALS),” Journal of Neuroimmunology, vol. 179, no. 1-2, pp. 87–93, 2006.
[37]
R. Zhang, R. G. Miller, R. Gascon et al., “Circulating endotoxin and systemic immune activation in sporadic Amyotrophic Lateral Sclerosis (sALS),” Journal of Neuroimmunology, vol. 206, no. 1-2, pp. 121–124, 2009.
[38]
V. Swarup, D. Phaneuf, N Dupré, et al., “Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways,” The Journal of Experimental Medicine, vol. 208, no. 12, pp. 2429–2447, 2011.
[39]
E. D. Hall, J. A. Oostveen, and M. E. Gurney, “Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS,” Glia, vol. 23, no. 3, pp. 249–256, 1998.
[40]
I. M. Chiu, A. Chen, Y. Zheng et al., “T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 46, pp. 17913–17918, 2008.
[41]
D. R. Beers, J. S. Henkel, W. Zhao, J. Wang, and S. H. Appel, “CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 40, pp. 15558–15563, 2008.
[42]
S. Zhu, I. G. Stavrovskaya, M. Drozda et al., “Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice,” Nature, vol. 417, no. 6884, pp. 74–78, 2002.
[43]
L. Van Den Bosch, P. Tilkin, G. Lemmens, and W. Robberecht, “Minocycline delays disease onset and mortality in a transgenic model of ALS,” NeuroReport, vol. 13, no. 8, pp. 1067–1070, 2002.
[44]
J. Kriz, M. D. Nguyen, and J. P. Julien, “Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis,” Neurobiology of Disease, vol. 10, no. 3, pp. 268–278, 2002.
[45]
Q. Xiao, W. Zhao, D. R. Beers et al., “Mutant SOD1G93A microglia are more neurotoxic relative to wild-type microglia,” Journal of Neurochemistry, vol. 102, no. 6, pp. 2008–2019, 2007.
[46]
G. Gowing, F. Dequen, G. Soucy, and J. P. Julien, “Absence of tumor necrosis factor-α does not affect motor neuron disease caused by superoxide dismutase 1 mutations,” Journal of Neuroscience, vol. 26, no. 44, pp. 11397–11402, 2006.
[47]
G. Gowing, T. Philips, B. Van Wijmeersch et al., “Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase,” Journal of Neuroscience, vol. 28, no. 41, pp. 10234–10244, 2008.
[48]
D. R. Beers, W. Zhao, B. Liao et al., “Neuroinflammation modulates distinct regional and temporal clinical responses in ALS mice,” Brain, Behavior, and Immunity, vol. 25, no. 5, pp. 1025–1035, 2011.
[49]
J. S. Henkel, D. R. Beers, W. Zhao, and S. H. Appel, “Microglia in ALS: the good, the bad, and the resting,” Journal of Neuroimmune Pharmacology, vol. 4, no. 4, pp. 389–398, 2009.
[50]
R. Banerjee, R. L. Mosley, A. D. Reynolds et al., “Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice,” PLoS One, vol. 3, no. 7, Article ID e2740, 2008.
[51]
D. R. Beers, J. S. Henkel, W. Zhao et al., “Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis,” Brain, vol. 134, pp. 1293–1314, 2011.
[52]
D. A. Hume, “The mononuclear phagocyte system,” Current Opinion in Immunology, vol. 18, no. 1, pp. 49–53, 2006.
[53]
L. J. Lawson, V. H. Perry, and S. Gordon, “Turnover of resident microglia in the normal adult mouse brain,” Neuroscience, vol. 48, no. 2, pp. 405–415, 1992.
[54]
W. F. Hickey and H. Kimura, “Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo,” Science, vol. 239, no. 4837, pp. 290–292, 1988.
[55]
D. W. Kennedy and J. L. Abkowitz, “Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model,” Blood, vol. 90, no. 3, pp. 986–993, 1997.
[56]
L. Vallières and P. E. Sawchenko, “Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity,” Journal of Neuroscience, vol. 23, no. 12, pp. 5197–5207, 2003.
[57]
C. A. B. Lewis, J. N. Solomon, F. M. Rossi, and C. Krieger, “Bone marrow-derived cells in the central nervous system of a mouse model of amyotrophic lateral sclerosis are associated with blood vessels and express CX3CR1,” Glia, vol. 57, no. 13, pp. 1410–1419, 2009.
[58]
A. Mildner, H. Schmidt, M. Nitsche et al., “Microglia in the adult brain arise from Ly-6 CCR2+ monocytes only under defined host conditions,” Nature Neuroscience, vol. 10, no. 12, pp. 1544–1553, 2007.
[59]
Y. Q. Li, P. Chen, V. Jain, R. M. Reilly, and C. S. Wong, “Early radiation-induced endothelial cell loss and blood-spinal cord barrier breakdown in the rat spinal cord,” Radiation Research, vol. 161, no. 2, pp. 143–152, 2004.
[60]
B. Ajami, J. L. Bennett, C. Krieger, W. Tetzlaff, and F. M. V. Rossi, “Local self-renewal can sustain CNS microglia maintenance and function throughout adult life,” Nature Neuroscience, vol. 10, no. 12, pp. 1538–1543, 2007.
[61]
M. Massengale, A. J. Wagers, H. Vogel, and I. L. Weissman, “Hematopoietic cells maintain hematopoietic fates upon entering the brain,” Journal of Experimental Medicine, vol. 201, no. 10, pp. 1579–1589, 2005.
[62]
B. Ajami, J. L. Bennett, C. Krieger, K. M. McNagny, and F. M. V. Rossi, “Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool,” Nature Neuroscience, vol. 141, no. 9, pp. 142–149, 2011.
