**5. References**

384 Amyotrophic Lateral Sclerosis

2006) by enhancing EAAT2 transcription (Lee et al., 2008). In addition, EAAT2 is also expressed by other cells types than astrocytes alone (Anderson and Swanson, 2000), which are not targeted in this genetic experimental design. Interestingly, removal of mutant SOD1 from astrocytes leads to prolonged survival without affecting astrogliosis, but does preserve

The beneficial effect of EAAT2 is often used as an explanation of positive effects found by cell transfers in ALS model rodents. For instance, the systemic transplantation of c-kit positive cell from bone marrow in mutant SOD1 mice significantly increased the lifespan, which is, at least in part, attributed to increased EAAT2 expression induced by the transferred cells (Corti et al., 2010). The same holds true for the prolonged survival of ALS rats when treated with focal transplantation-based astrocyte replacement with wild type glial-restricted precursors (GRPs) (Lepore et al., 2008b). This study also focussed on EAAT2 by also transplanting EAAT2 overexpressing GRPs and EAAT2 null GRPs. The ALS mice treated with the EAAT2 overexpressing GRPs showed no additional increase of lifespan compared to wild type GRP treated ALS mice (already increased compared to controls). Intriguingly, this positive effect of transplantation of the wild type GRPs is diminished in mice transplanted with EAAT2 null GRPs (Lepore et al., 2008b). In addition, co-cultures of human adipose-derived stem cells with astrocytes induce higher levels of EAAT2 in astrocytes (Gu et al., 2010), though this treatment has not (yet) been shown to affect motor

After the release of glutamate from the pre-synaptic neuron into the synaptic cleft, glutamate binds to NMDA, AMPA receptors or the metabotropic receptors. High levels of calcium entering through AMPA receptors into the post-synaptic neuron can cause neuronal death. The AMPA receptor is formed as a tetramer combining, usually pairwise, a combination of its four different subunits (glutamate receptor unit 1-4 (GluR1-4)) (Shi et al., 1999). Each subunit can bind glutamate and the channel opens after occupation of at least 2 binding locations (Mayer, 2005). The importance of this receptor in ALS is demonstrated by the ablation of glutamate induced apoptosis in cortical neurons in vitro (Cid et al., 2003) and in vivo when administering an AMPA receptor antagonist (Van Damme et al., 2003; Tortarolo et al., 2006). The AMPA receptor plays an imperative role in excitotoxicity by its calcium permeability that is determined by the incorporation of the GluR2 subunit in the receptor complex. In most conditions, the AMPA receptor complex contains at least one GluR2 subunit and it prevents the influx of extracellular calcium into the neuron (Seeburg et al., 2001). In contrast, receptors lacking the GluR2 subunit are highly calcium permeable (Seeburg et al., 2001). A general decrease of GluR2 is found in ALS model mice, portraying an increased vulnerability of these mice to excitotoxic insults (Tortarolo et al., 2006; Zhao et al., 2008). The role of GluR2 in ALS is investigated by genetically ablating GluR2 in ALS mice, which decreases survival in vivo and decreases cell survival in vitro (Van Damme et al., 2005). The opposite has been shown by up-regulating GluR2 expression in motor neurons of ALS mice, as hereby survival is increased (Tateno et al., 2002). In addition, pharmacological inhibition of the AMPA receptor prolonged survival in ALS model mice (Van Damme et al., 2003;

EAAT2 levels potentially explaining the extended lifespan (Wang et al., 2011a).

**3.5 Astrocytes in excitotoxicity in ALS: AMPA receptor permeability** 

**3.4 Astrocytic replacement therapy in ALS mice** 

neuron survival in vitro or in vivo.

Tortarolo et al., 2006).


The Astrocytic Contribution in ALS: Inflammation and Excitotoxicity 387

Ganel, R., Ho, T., Maragakis, N.J., Jackson, M., Steiner, J.P., and Rothstein, J.D. (2006).

Gowing, G., Dequen, F., Soucy, G., and Julien, J.P. (2006). Absence of tumor necrosis factor-

Gowing, G., Lalancette-Hebert, M., Audet, J.N., Dequen, F., and Julien, J.P. (2009).

Gowing, G., Philips, T., Van Wijmeersch, B., Audet, J.N., Dewil, M., Van Den Bosch, L.,

Gu, R., Hou, X., Pang, R., Li, L., Chen, F., Geng, J., Xu, Y., and Zhang, C. (2010). Human

SOD1(G93A)-bearing astrocytes. *Biochem Biophys Res Commun* 393, 481-486. Guo, H., Lai, L., Butchbach, M.E., Stockinger, M.P., Shan, X., Bishop, G.A., and Lin, C.L.

Guo, Y., Duan, W., Li, Z., Huang, J., Yin, Y., Zhang, K., Wang, Q., Zhang, Z., and Li, C.

Gurney, M.E., Pu, H., Chiu, A.Y., Dal Canto, M.C., Polchow, C.Y., Alexander, D.D.,

Haidet-Phillips, A.M., Hester, M.E., Miranda, C.J., Meyer, K., Braun, L., Frakes, A., Song, S.,

Hensley, K., Abdel-Moaty, H., Hunter, J., Mhatre, M., Mou, S., Nguyen, K., Potapova, T.,

for studies of glial inflammation. *J Neuroinflammation* 3, 2.

certainty of disease diagnoses. *Acta Neurol Scand* 121, 120-126.

doi:10.1038/cddis.2011.11.

*Genet* 12, 2519-2532.

*FEBS Lett* 584, 1615-1622.

*Science* 264, 1772-1775.

nbt.1957

mutations. *J Neurosci* 26, 11397-11402.

dismutase. *Exp Neurol* 220, 267-275.

amyotrophic lateral sclerosis. *Cell Calcium* 47, 165-174.

fluid of amyotrophic lateral sclerosis patients. Relationship with the degree of

Selective up-regulation of the glial Na+-dependent glutamate transporter GLT1 by a neuroimmunophilin ligand results in neuroprotection. *Neurobiol Dis* 21, 556-567. Genestine, M., Caricati, E., Fico, A., Richelme, S., Hassani, H., Sunyach, C., Lamballe, F.,

Panzica, G.C., Pettmann, B., Helmbacher, F.*, et al.* (2011). Enhanced neuronal Met signalling levels in ALS mice delay disease onset. *Cell Death Dis* 2, e130;

alpha does not affect motor neuron disease caused by superoxide dismutase 1

Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide

Billiau, A.D., Robberecht, W., and Julien, J.P. (2008). Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. *J Neurosci* 28, 10234-10244. Grosskreutz, J., Van Den Bosch, L., and Keller, B.U. (2010). Calcium dysregulation in

adipose-derived stem cells enhance the glutamate uptake function of GLT1 in

(2003). Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. *Hum Mol* 

(2010). Decreased GLT-1 and increased SOD1 and HO-1 expression in astrocytes contribute to lumbar spinal cord vulnerability of SOD1-G93A transgenic mice.

Caliendo, J., Hentati, A., Kwon, Y.W., Deng, H.X.*, et al.* (1994). Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.

Likhite, S., Murtha, M.J., Foust, K.D.*, et al.* (2011). Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. *Nat Biotechnol* doi: 10.1038/

Pye, Q.N., Qi, M., Rice, H.*, et al.* (2006). Primary glia expressing the G93A-SOD1 mutation present a neuroinflammatory phenotype and provide a cellular system

GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. *J Neurochem* 79, 737-746.


Bensimon, G., Lacomblez, L., and Meininger, V. (1994). A controlled trial of riluzole in

Boillee, S., Vande Velde, C., and Cleveland, D.W. (2006a). ALS: a disease of motor neurons

Boillee, S., Yamanaka, K., Lobsiger, C.S., Copeland, N.G., Jenkins, N.A., Kassiotis, G.,

Bristol, L.A., and Rothstein, J.D. (1996). Glutamate transporter gene expression in

Bruijn, L.I., Miller, T.M., and Cleveland, D.W. (2004). Unraveling the mechanisms involved in motor neuron degeneration in ALS. *Annu Rev Neurosci* 27, 723-749. Casula, M., Iyer, A.M., Spliet, W.G., Anink, J.J., Steentjes, K., Sta, M., Troost, D., and Aronica,

Chiu, I.M., Chen, A., Zheng, Y., Kosaras, B., Tsiftsoglou, S.A., Vartanian, T.K., Brown, R.H.,

Corti, S., Nizzardo, M., Nardini, M., Donadoni, C., Salani, S., Simone, C., Falcone, M.,

Crosio, C., Valle, C., Casciati, A., Iaccarino, C., and Carri, M.T. (2011). Astroglial inhibition of

Del Bo, R., Ghezzi, S., Corti, S., Pandolfo, M., Ranieri, M., Santoro, D., Ghione, I., Prelle, A.,

Drachman, D.B., Frank, K., Dykes-Hoberg, M., Teismann, P., Almer, G., Przedborski, S., and

Fiszman, M.L., Ricart, K.C., Latini, A., Rodriguez, G., and Sica, R.E. (2010). In vitro

determined by motor neurons and microglia. *Science* 312, 1389-1392. Boucherie, C., Schafer, S., Lavand'homme, P., Maloteaux, J.M., and Hermans, E. (2009).

amyotrophic lateral sclerosis motor cortex. *Ann Neurol* 39, 676-679.

and their nonneuronal neighbors. *Neuron* 52, 39-59.

amyotrophic lateral sclerosis. *J Neurosci Res* 87, 2034-2046.

amyotrophic lateral sclerosis. *J Neurol Sci* 206, 91-95.

*Neurochem* 79, 737-746.

tissue. *Neuroscience* 179, 233-243.

*Genet* 19, 3782-3796.

journal.pone.0017187.

*J Neurol* 16, 727-732.

*Neurodegener Dis* 4, 431-442.

591.

GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. *J* 

amyotrophic lateral sclerosis. ALS/Riluzole Study Group. *N Engl J Med* 330, 585-

Kollias, G., and Cleveland, D.W. (2006b). Onset and progression in inherited ALS

Chimerization of astroglial population in the lumbar spinal cord after mesenchymal stem cell transplantation prolongs survival in a rat model of

E. (2011). Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord

Jr., and Carroll, M.C. (2008). T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. *Proc Natl Acad Sci U S A* 105, 17913-17918. Cid, C., Alvarez-Cermeno, J.C., Regidor, I., Salinas, M., and Alcazar, A. (2003). Low

concentrations of glutamate induce apoptosis in cultured neurons: implications for

Riboldi, G., Govoni, A., Bresolin, N.*, et al.* (2010). Systemic transplantation of c-kit+ cells exerts a therapeutic effect in a model of amyotrophic lateral sclerosis. *Hum Mol* 

NF-kappaB does not ameliorate disease onset and progression in a mouse model for amyotrophic lateral sclerosis (ALS). *PLoS One* 6(3): e17187. doi:10.1371/

Orsetti, V., Mancuso, M.*, et al.* (2009). TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations. *Eur* 

Rothstein, J.D. (2002). Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. *Ann Neurol* 52, 771-778. Fischer, L.R., and Glass, J.D. (2007). Axonal degeneration in motor neuron disease.

neurotoxic properties and excitatory aminoacids concentration in the cerebrospinal

fluid of amyotrophic lateral sclerosis patients. Relationship with the degree of certainty of disease diagnoses. *Acta Neurol Scand* 121, 120-126.


The Astrocytic Contribution in ALS: Inflammation and Excitotoxicity 389

Lepore, A.C., Rauck, B., Dejea, C., Pardo, A.C., Rao, M.S., Rothstein, J.D., and Maragakis,

Liang, X., Wang, Q., Shi, J., Lokteva, L., Breyer, R.M., Montine, T.J., and Andreasson, K.

Logroscino, G., Traynor, B.J., Hardiman, O., Chio, A., Mitchell, D., Swingler, R.J., Millul, A.,

Maessen, M., Veldink, J.H., van den Berg, L.H., Schouten, H.J., van der Wal, G., and

Marchetto, M.C., Muotri, A.R., Mu, Y., Smith, A.M., Cezar, G.G., and Gage, F.H. (2008).

ALS, heart failure, and cancer patients. *J Neurol* 257, 1192-1198.

derived from human embryonic stem cells. *Cell Stem Cell* 3, 649-657. Maruyama, H., Morino, H., Ito, H., Izumi, Y., Kato, H., Watanabe, Y., Kinoshita, Y., Kamada,

Mayer, M.L. (2005). Glutamate receptor ion channels. *Curr Opin Neurobiol* 15, 282-288. Miller, R.G., Mitchell, J.D., Lyon, M., and Moore, D.H. (2007). Riluzole for amyotrophic

in a model of motor neuron disease. *Nat Neurosci* 11, 1294-1301.

106, 4465-4470.

CD001447.

493-502.

*Neurol* 256, 1228-1235.

*Neurol* 220, 191-197.

*J Neurol Neurosurg Psychiatry* 81(4):385-90

sclerosis. *Nature* 465, 223-226.

N.J. (2008b). Focal transplantation-based astrocyte replacement is neuroprotective

(2008). The prostaglandin E2 EP2 receptor accelerates disease progression and inflammation in a model of amyotrophic lateral sclerosis. *Ann Neurol* 64, 304-314. Lobsiger, C.S., Boillee, S., McAlonis-Downes, M., Khan, A.M., Feltri, M.L., Yamanaka, K.,

and Cleveland, D.W. (2009). Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice. *Proc Natl Acad Sci U S A* 

Benn, E., and Beghi, E. (2010). Incidence of amyotrophic lateral sclerosis in Europe.

Onwuteaka-Philipsen, B.D. (2010). Requests for euthanasia: origin of suffering in

Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons

M., Nodera, H., Suzuki, H.*, et al.* Mutations of optineurin in amyotrophic lateral

lateral sclerosis (ALS)/motor neuron disease (MND). *Cochrane Database Syst Rev*,

Development of ALS-like disease in SOD-1 mice deficient of B lymphocytes. *J* 

M.F., and Kiaei, M. (2009). Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis. *Exp* 

motor neuron disease by chronic stimulation of innate immunity in a mouse model

Inflammation in ALS and SMA: sorting out the good from the evil. *Neurobiol Dis* 37,

N.J. (2006). Loss of the astrocyte glutamate transporter GLT1 modifies disease in

C., Mazzini, L., and Bachetti, T. (2000). Circulating levels of tumour necrosis factor-

Naor, S., Keren, Z., Bronshtein, T., Goren, E., Machluf, M., and Melamed, D. (2009).

Neymotin, A., Petri, S., Calingasan, N.Y., Wille, E., Schafer, P., Stewart, C., Hensley, K., Beal,

Nguyen, M.D., D'Aigle, T., Gowing, G., Julien, J.P., and Rivest, S. (2004). Exacerbation of

Papadimitriou, D., Le Verche, V., Jacquier, A., Ikiz, B., Przedborski, S., and Re, D.B. (2010).

Pardo, A.C., Wong, V., Benson, L.M., Dykes, M., Tanaka, K., Rothstein, J.D., and Maragakis,

Philips, T., and Robberecht, W. (2011). Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. *Lancet Neurol* 10, 253-263. Poloni, M., Facchetti, D., Mai, R., Micheli, A., Agnoletti, L., Francolini, G., Mora, G., Camana,

of amyotrophic lateral sclerosis. *J Neurosci* 24, 1340-1349.

SOD1(G93A) mice. *Exp Neurol* 201, 120-130.


Howland, D.S., Liu, J., She, Y., Goad, B., Maragakis, N.J., Kim, B., Erickson, J., Kulik, J.,

Jaarsma, D., Teuling, E., Haasdijk, E.D., De Zeeuw, C.I., and Hoogenraad, C.C. (2008).

Keller, A.F., Gravel, M., and Kriz, J. (2009). Live imaging of amyotrophic lateral sclerosis

Keller, A.F., Gravel, M., and Kriz, J. (2011). Treatment with minocycline after disease onset

Kiaei, M., Kipiani, K., Petri, S., Chen, J., Calingasan, N.Y., and Beal, M.F. (2005). Celastrol

Kiaei, M., Petri, S., Kipiani, K., Gardian, G., Choi, D.K., Chen, J., Calingasan, N.Y., Schafer,

Kriz, J., Nguyen, M.D., and Julien, J.P. (2002). Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. *Neurobiol Dis* 10, 268-278. Kotchoubey, B., Lang, S., Winter, S., and Birbaumer, N. (2003). Cognitive processing in

Kwiatkowski, T.J., Jr., Bosco, D.A., Leclerc, A.L., Tamrazian, E., Vanderburg, C.R., Russ, C.,

Laake, J.H., Slyngstad, T.A., Haug, F.M., and Ottersen, O.P. (1995). Glutamine from glial

Lee, S.G., Su, Z.Z., Emdad, L., Gupta, P., Sarkar, D., Borjabad, A., Volsky, D.J., and Fisher,

Lepore, A.C., Dejea, C., Carmen, J., Rauck, B., Kerr, D.A., Sofroniew, M.V., and Maragakis,

amyotrophic lateral sclerosis in transgenic mice. *J Neurosci* 28, 2075-2088. Johnson, J.O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V.M., Trojanowski, J.Q.,

(ALS). *Proc Natl Acad Sci U S A* 99, 1604-1609.

Schwann cells. *Glia* 57, 1130-1142.

*Neurol* 228, 69-79.

2467-2473.

551-558.

*Science* 323, 1205-1208.

*Chem* 283, 13116-13123.

*Neurol* 211, 423-432.

mutations as a cause of familial ALS. *Neuron* 68, 857-864.

amyotrophic lateral sclerosis. *Neurodegener Dis* 2, 246-254.

Sclerosis/Riluzole Study Group II. *Lancet* 347, 1425-1431.

DeVito, L., Psaltis, G.*, et al.* (2002). Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis

Neuron-specific expression of mutant superoxide dismutase is sufficient to induce

Gibbs, J.R., Brunetti, M., Gronka, S., Wuu, J.*, et al.* Exome sequencing reveals VCP

pathogenesis: disease onset is characterized by marked induction of GFAP in

alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice. *Exp* 

blocks neuronal cell death and extends life in transgenic mouse model of

P., Muller, G.W., Stewart, C.*, et al.* (2006). Thalidomide and lenalidomide extend survival in a transgenic mouse model of amyotrophic lateral sclerosis. *J Neurosci* 26,

completely paralyzed patients with amyotrophic lateral sclerosis. *Eur J Neurol* 10,

Davis, A., Gilchrist, J., Kasarskis, E.J., Munsat, T.*, et al.* (2009). Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.

cells is essential for the maintenance of the nerve terminal pool of glutamate: immunogold evidence from hippocampal slice cultures. *J Neurochem* 65, 871-881. Lacomblez, L., Bensimon, G., Leigh, P.N., Guillet, P., and Meininger, V. (1996). Dose-ranging

study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral

P.B. (2008). Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. *J Biol* 

N.J. (2008a). Selective ablation of proliferating astrocytes does not affect disease outcome in either acute or chronic models of motor neuron degeneration. *Exp* 


The Astrocytic Contribution in ALS: Inflammation and Excitotoxicity 391

Spreux-Varoquaux, O., Bensimon, G., Lacomblez, L., Salachas, F., Pradat, P.F., Le Forestier,

Sta, M., Sylva-Steenland, R.M., Casula, M., de Jong, J.M., Troost, D., Aronica, E., and Baas, F.

Staats, K.A., and Van Den Bosch, L. (2009). Astrocytes in amyotrophic lateral sclerosis: direct

Tanaka, K., Watase, K., Manabe, T., Yamada, K., Watanabe, M., Takahashi, K., Iwama, H.,

Tateishi, T., Yamasaki, R., Tanaka, M., Matsushita, T., Kikuchi, H., Isobe, N., Ohyagi, Y., and

Tateno, M., Sugimoto, H., Tanaka, S., Itohara, H., Hama, A., Miyawaki, R.M., Shin, M.M.,

Tortarolo, M., Crossthwaite, A.J., Conforti, L., Spencer, J.P., Williams, R.J., Bendotti, C., and

Tortarolo, M., Grignaschi, G., Calvaresi, N., Zennaro, E., Spaltro, G., Colovic, M., Fracasso,

Tovar, Y.R.L.B., Santa-Cruz, L.D., Zepeda, A., and Tapia, R. (2009). Chronic elevation of

Van Damme, P., Bogaert, E., Dewil, M., Hersmus, N., Kiraly, D., Scheveneels, W., Bockx, I.,

Van Damme, P., Braeken, D., Callewaert, G., Robberecht, W., and Van Den Bosch, L. (2005).

Van Damme, P., Leyssen, M., Callewaert, G., Robberecht, W., and Van Den Bosch, L. (2003).

Van Deerlin, V.M., Leverenz, J.B., Bekris, L.M., Bird, T.D., Yuan, W., Elman, L.B., Clay, D.,

amyotrophic lateral sclerosis. *J Neuropathol Exp Neurol* 64, 605-612.

model of amyotrophic lateral sclerosis. *Neurosci Lett* 343, 81-84.

complement activation. *Neurobiol Dis* 42, 211-220.

effects on motor neuron survival. *J Biol Phys* 35(4): p. 337-46.

amyotrophic lateral sclerosis. *J Neuroimmunol* 222, 76-81.

involvement of oxidative stress. *J Neurochem* 88, 481-493.

sclerosis-like disease. *J Neurosci Res* 83, 134-146.

motoneurons in vivo. *Neurochem Int* 54, 186-191.

*Sci U S A* 104, 14825-14830.

in an ALS transgenic mouse model. *Soc for Neurosci Abstr* 789.21

193, 73-78.

1702.

N., Marouan, A., Dib, M., and Meininger, V. (2002). Glutamate levels in cerebrospinal fluid in amyotrophic lateral sclerosis: a reappraisal using a new HPLC method with coulometric detection in a large cohort of patients. *J Neurol Sci* 

(2011). Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of

Nishikawa, T., Ichihara, N., Kikuchi, T.*, et al.* (1997). Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. *Science* 276, 1699-

Kira, J. (2010). CSF chemokine alterations related to the clinical course of

Masumada, T., Aosaki, H., Misawa, R.*, et al.* (2002). GluR2 overexpression in motor neurons renders AMPA receptors impermeable to calcium and delays disease onset

Rattray, M. (2004). Expression of SOD1 G93A or wild-type SOD1 in primary cultures of astrocytes down-regulates the glutamate transporter GLT-1: lack of

C., Guiso, G., Elger, B., Schneider, H.*, et al.* (2006). Glutamate AMPA receptors change in motor neurons of SOD1(G93A) transgenic mice and their inhibition by a noncompetitive antagonist ameliorates the progression of amytrophic lateral

extracellular glutamate due to transport blockade is innocuous for spinal

Braeken, D., Verpoorten, N., Verhoeven, K.*, et al.* (2007). Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. *Proc Natl Acad* 

GluR2 deficiency accelerates motor neuron degeneration in a mouse model of

The AMPA receptor antagonist NBQX prolongs survival in a transgenic mouse

Wood, E.M., Chen-Plotkin, A.S., Martinez-Lage, M.*, et al.* (2008). TARDBP

alpha and its soluble receptors are increased in the blood of patients with amyotrophic lateral sclerosis. *Neurosci Lett* 287, 211-214.


Ransohoff, R.M., and Cardona, A.E. (2010). The myeloid cells of the central nervous system

Raoul, C., Buhler, E., Sadeghi, C., Jacquier, A., Aebischer, P., Pettmann, B., Henderson, C.E.,

Raoul, C., Estevez, A.G., Nishimune, H., Cleveland, D.W., deLapeyriere, O., Henderson,

Reaume, A.G., Elliott, J.L., Hoffman, E.K., Kowall, N.W., Ferrante, R.J., Siwek, D.F., Wilcox,

Rothstein, J.D., Patel, S., Regan, M.R., Haenggeli, C., Huang, Y.H., Bergles, D.E., Jin, L.,

Rutherford, N.J., Zhang, Y.J., Baker, M., Gass, J.M., Finch, N.A., Xu, Y.F., Stewart, H., Kelley,

patients with familial amyotrophic lateral sclerosis. *PLoS Genet* 4, e1000193. Sala, G., Beretta, S., Ceresa, C., Mattavelli, L., Zoia, C., Tremolizzo, L., Ferri, A., Carri, M.T.,

Sasaki, S., Warita, H., Abe, K., Komori, T., and Iwata, M. (2001). EAAT1 and EAAT2

Schiffer, D., Cordera, S., Cavalla, P., and Migheli, A. (1996). Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis. *J Neurol Sci* 139 Suppl, 27-33. Seeburg, P.H., Single, F., Kuner, T., Higuchi, M., and Sprengel, R. (2001). Genetic

Shefner, J.M., Reaume, A.G., Flood, D.G., Scott, R.W., Kowall, N.W., Ferrante, R.J., Siwek,

Shi, S.H., Hayashi, Y., Petralia, R.S., Zaman, S.H., Wenthold, R.J., Svoboda, K., and Malinow,

Siniscalchi, A., Zona, C., Sancesario, G., D'Angelo, E., Zeng, Y.C., Mercuri, N.B., and

histological analysis in an in vitro model of ischemia. *Synapse* 32, 147-152.

NMDA receptor activation. *Science* 284, 1811-1816.

enhanced cell death after axonal injury. *Nat Genet* 13, 43-47.

amyotrophic lateral sclerosis. *Neurosci Lett* 287, 211-214.

parenchyma. *Nature* 468, 253-262.

*Acad Sci U S A* 103, 6007-6012.

*Neurochem Int* 46, 227-234.

mouse. *Brain Res* 907, 233-243.

*Neurology* 53, 1239-1246.

12, 1359-1362.

35, 1067-1083.

73-77.

alpha and its soluble receptors are increased in the blood of patients with

and Haase, G. (2006). Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL. *Proc Natl* 

C.E., Haase, G., and Pettmann, B. (2002). Motoneuron death triggered by a specific pathway downstream of Fas. potentiation by ALS-linked SOD1 mutations. *Neuron* 

H.M., Flood, D.G., Beal, M.F., Brown, R.H., Jr.*, et al.* (1996). Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit

Dykes Hoberg, M., Vidensky, S., Chung, D.S.*, et al.* (2005). Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. *Nature* 433,

B.J., Kuntz, K., Crook, R.J.*, et al.* (2008). Novel mutations in TARDBP (TDP-43) in

and Ferrarese, C. (2005). Impairment of glutamate transport and increased vulnerability to oxidative stress in neuroblastoma SH-SY5Y cells expressing a Cu,Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis.

immunoreactivity in transgenic mice with a G93A mutant SOD1 gene. *Neuroreport* 

manipulation of key determinants of ion flow in glutamate receptor channels in the

D.F., Upton-Rice, M., and Brown, R.H., Jr. (1999). Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy.

R. (1999). Rapid spine delivery and redistribution of AMPA receptors after synaptic

Bernardi, G. (1999). Neuroprotective effects of riluzole: an electrophysiological and


**17** 

*Australia* 

**Innate Immunity in ALS** 

*1School of Biomedical Sciences,* 

John D. Lee1, Jia Y. Lee1, Stephen M. Taylor1, Peter G. Noakes1, 2 and Trent M. Woodruff1

*2Queensland Brain Institute, University of Queensland,* 

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is the most common form of motor neuron disease. It is a debilitating, late onset neurodegenerative disorder that is characterized by the progressive death of upper and α-motor neurons within the central nervous system (CNS) (Bruijn and Cleveland, 1996). This results in symptoms of muscle weakness and atrophy of skeletal muscles, leading to paralysis and eventual death due to failure of respiratory muscles (Cozzolino et al., 2008). ALS has a prevalence of approximately 1~2 per 100,000 worldwide with males being more susceptible than females (1.3 ~ 1.6: 1) (Strong, 2003, Woodruff et al., 2008b, Worms, 2001). The majority of ALS cases (~90%) are thought to be sporadic with unknown aetiology and no robust environmental risk factors, with the remaining 10% being familial ALS. Of this 10%, approximately 20% have been linked to dominant mis-sense point mutations in the Copper/Zinc superoxide dismutase 1 (SOD1) gene which results in a gain of unidentified deleterious properties (Rosen et al., 1993). The two aetiologies of ALS (i.e. sporadic and familial) are indistinguishable on the basis of their clinical and pathological features, including progressive muscle weakness, atrophy and spasticity, each of which reflects the degeneration and death of upper and α-motor neurons (Boillee et al., 2006). The mechanisms leading to ALS are still unclear but theories have suggested that glutamate excitoxicity, oxidative stress, protein aggregation, mitochondrial dysfunction, cytoskeletal abnormalities and neuro-inflammation may all play a role (Bruijn et al., 2004). The present chapter will review the role of innate immune system, in particular the complement system, during the disease progression of ALS. It will review evidence for an involvement of the innate immune Toll-like receptor (TLR) system and receptor for advanced glycosylation end products (RAGE) in ALS patients and animal models of ALS. It will also comprehensively evaluate the role of the innate immune complement cascade in this disease. Finally, the future therapeutic possibilities for ALS, aimed at targeting components of the innate immune system will be discussed. We provide compelling evidence for specific inhibitors of complement C5a

Innate immunity is an evolutionary ancient system that provides the host with immediately available defence mechanisms. It is a rapid and coordinated cascade of reactions by host

**1. Introduction** 

receptors as novel treatment strategies for ALS.

**2. Innate immunity in neurodegenerative disease** 

mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. *Lancet Neurol* 7, 409-416.

