Inflammation in ALS/FTD pathogenesis

1.

Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM (2011) Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14:1142–1149. https://doi.org/10.1038/nn.2887 CrossRefPubMed

2.

Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10:1538–1543. https://doi.org/10.1038/nn2014 CrossRefPubMed

3.

Akizuki M, Yamashita H, Uemura K, Maruyama H, Kawakami H, Ito H et al (2013) Optineurin suppression causes neuronal cell death via NF-kappaB pathway. J Neurochem 126:699–704. https://doi.org/10.1111/jnc.12326 CrossRefPubMed

4.

Alexianu ME, Kozovska M, Appel SH (2001) Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57:1282–1289CrossRefPubMed

5.

Alshikho MJ, Zurcher NR, Loggia ML, Cernasov P, Reynolds B, Pijanowski O et al (2018) Integrated MRI and [(11) C]-PBR28 PET imaging in amyotrophic lateral sclerosis. Ann Neurol. https://doi.org/10.1002/ana.25251

6.

Amick J, Roczniak-Ferguson A, Ferguson SM (2016) C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Mol Biol Cell 27:3040–3051. https://doi.org/10.1091/mbc.E16-01-0003 CrossRefPubMedPubMedCentral

7.

Appel SH, Smith RG, Alexianu M, Siklos L, Engelhardt J, Colom LV et al (1995) Increased intracellular calcium triggered by immune mechanisms in amyotrophic lateral sclerosis. Clin Neurosci 3:368–374PubMed

8.

Appel SH, Stewart SS, Appel V, Harati Y, Mietlowski W, Weiss W et al (1988) A double-blind study of the effectiveness of cyclosporine in amyotrophic lateral sclerosis. Arch Neurol 45:381–386CrossRefPubMed

9.

Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M et al (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77:639–646. https://doi.org/10.1016/j.neuron.2013.02.004 CrossRefPubMedPubMedCentral

10.

Atanasio A, Decman V, White D, Ramos M, Ikiz B, Lee HC et al (2016) C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci Rep 6:23204. https://doi.org/10.1038/srep23204 CrossRefPubMedPubMedCentral

11.

Baumann J (1965) Results of treatment of certain diseases of the central nervous system with ACTH and corticosteroids. Acta Neurol Scand Suppl 13(Pt 2):453–461PubMed

12.

Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA et al (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 103:16021–16026. https://doi.org/10.1073/pnas.0607423103 CrossRefPubMedPubMedCentral

13.

Beers DR, Zhao W, Appel SH (2018) The role of regulatory T lymphocytes in amyotrophic lateral sclerosis. JAMA Neurol 75:656–658. https://doi.org/10.1001/jamaneurol.2018.0043 CrossRefPubMed

14.

Beers DR, Zhao W, Wang J, Zhang X, Wen S, Neal D et al (2017) ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight 2:e89530. https://doi.org/10.1172/jci.insight.89530 CrossRefPubMedPubMedCentral

15.

Ben Younes-Chennoufi A, Rozier A, Dib M, Bouche P, Lacomblez L, Mombo N et al (1995) Anti-sulfoglucuronyl paragloboside IgM antibodies in amyotrophic lateral sclerosis. J Neuroimmunol 57:111–115CrossRefPubMed

16.

Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB et al (2016) New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci USA 113:E1738–E1746. https://doi.org/10.1073/pnas.1525528113 CrossRefPubMedPubMedCentral

17.

Bettencourt C, Houlden H (2015) Exome sequencing uncovers hidden pathways in familial and sporadic ALS. Nat Neurosci 18:611–613. https://doi.org/10.1038/nn.4012 CrossRefPubMed

18.

Bohlen CJ, Bennett FC, Tucker AF, Collins HY, Mulinyawe SB, Barres BA (2017) Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94(759–773):e758. https://doi.org/10.1016/j.neuron.2017.04.043 CrossRef

19.

Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G et al (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389–1392. https://doi.org/10.1126/science.1123511 CrossRefPubMed

20.

Bossu P, Salani F, Alberici A, Archetti S, Bellelli G, Galimberti D et al (2011) Loss of function mutations in the progranulin gene are related to pro-inflammatory cytokine dysregulation in frontotemporal lobar degeneration patients. J Neuroinflamm 8:65. https://doi.org/10.1186/1742-2094-8-65 CrossRef

21.

Brettschneider J, Toledo JB, Van Deerlin VM, Elman L, McCluskey L, Lee VM et al (2012) Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS One 7:e39216. https://doi.org/10.1371/journal.pone.0039216 CrossRefPubMedPubMedCentral

22.

Brown RH Jr, Al-Chalabi A (2017) Amyotrophic lateral sclerosis. N Engl J Med 377:1602. https://doi.org/10.1056/NEJMc1710379 CrossRefPubMed

23.

Brown RH Jr, Hauser SL, Harrington H, Weiner HL (1986) Failure of immunosuppression with a ten- to 14-day course of high-dose intravenous cyclophosphamide to alter the progression of amyotrophic lateral sclerosis. Arch Neurol 43:383–384CrossRefPubMed

24.

Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG et al (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338CrossRefPubMed

25.

Burberry A, Suzuki N, Wang JY, Moccia R, Mordes DA, Stewart MH et al (2016) Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci Transl Med 8:347ra393. https://doi.org/10.1126/scitranslmed.aaf6038 CrossRef

26.

Cagnin A, Rossor M, Sampson EL, Mackinnon T, Banati RB (2004) In vivo detection of microglial activation in frontotemporal dementia. Ann Neurol 56:894–897. https://doi.org/10.1002/ana.20332 CrossRefPubMed

27.

Cheng F, Wang HW, Cuenca A, Huang M, Ghansah T, Brayer J et al (2003) A critical role for Stat3 signaling in immune tolerance. Immunity 19:425–436CrossRefPubMed

28.

Chew TS, O’Shea NR, Sewell GW, Oehlers SH, Mulvey CM, Crosier PS et al (2015) Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis. Dis Models Mech 8:817–829. https://doi.org/10.1242/dmm.020362 CrossRef

29.

Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS et al (2015) Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347:1436–1441. https://doi.org/10.1126/science.aaa3650 CrossRefPubMedPubMedCentral

30.

Ciura S, Lattante S, Le Ber I, Latouche M, Tostivint H, Brice A et al (2013) Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann Neurol 74:180–187. https://doi.org/10.1002/ana.23946 CrossRefPubMed

31.

Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M et al (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302:113–117. https://doi.org/10.1126/science.1086071 CrossRefPubMed

32.

Coffelt SB, de Visser KE (2016) Revving up dendritic cells while braking PD-L1 to jump-start the cancer-immunity cycle motor. Immunity 44:722–724. https://doi.org/10.1016/j.immuni.2016.03.014 CrossRefPubMed

33.

Corcia P, Tauber C, Vercoullie J, Arlicot N, Prunier C, Praline J et al (2012) Molecular imaging of microglial activation in amyotrophic lateral sclerosis. PLoS One 7:e52941. https://doi.org/10.1371/journal.pone.0052941 CrossRefPubMedPubMedCentral

34.

DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256. https://doi.org/10.1016/j.neuron.2011.09.011 CrossRefPubMedPubMedCentral

35.

Donnenfeld H, Kascsak RJ, Bartfeld H (1984) Deposits of IgG and C3 in the spinal cord and motor cortex of ALS patients. J Neuroimmunol 6:51–57CrossRefPubMed

36.

Drachman DB, Chaudhry V, Cornblath D, Kuncl RW, Pestronk A, Clawson L et al (1994) Trial of immunosuppression in amyotrophic lateral sclerosis using total lymphoid irradiation. Ann Neurol 35:142–150. https://doi.org/10.1002/ana.410350205 CrossRefPubMed

37.

Duarte F, Binet S, Lacomblez L, Bouche P, Preud’homme JL, Meininger V (1991) Quantitative analysis of monoclonal immunoglobulins in serum of patients with amyotrophic lateral sclerosis. J Neurol Sci 104:88–91CrossRefPubMed

38.

Engelhardt JI, Tajti J, Appel SH (1993) Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch Neurol 50:30–36CrossRefPubMed

39.

Fang F, Al-Chalabi A, Ronnevi LO, Turner MR, Wirdefeldt K, Kamel F et al (2013) Amyotrophic lateral sclerosis and cancer: a register-based study in Sweden. Amyotroph Lateral Scler Motor Neuron Disord 14:362–368. https://doi.org/10.3109/21678421.2013.775309 CrossRef

40.

Faraco G, Park L, Anrather J, Iadecola C (2017) Brain perivascular macrophages: characterization and functional roles in health and disease. J Mol Med 95:1143–1152. https://doi.org/10.1007/s00109-017-1573-x CrossRefPubMed

41.

Faraco G, Sugiyama Y, Lane D, Garcia-Bonilla L, Chang H, Santisteban MM et al (2016) Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension. J Clin Investig 126:4674–4689. https://doi.org/10.1172/JCI86950 CrossRefPubMedPubMedCentral

42.

Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RA, Levina V et al (2014) C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet 23:3579–3595. https://doi.org/10.1093/hmg/ddu068 CrossRefPubMedPubMedCentral

43.

Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT et al (2003) IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4:491–496. https://doi.org/10.1038/ni921 CrossRefPubMed

44.

Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ et al (2014) Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis. Neuron 81:1009–1023. https://doi.org/10.1016/j.neuron.2014.01.013 CrossRefPubMedPubMedCentral

45.

Freedman DM, Wu J, Daugherty SE, Kuncl RW, Enewold LR, Pfeiffer RM (2014) The risk of amyotrophic lateral sclerosis after cancer in US elderly adults: a population-based prospective study. Int J Cancer 135:1745–1750. https://doi.org/10.1002/ijc.28795 CrossRefPubMedPubMedCentral

46.

Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Muller K et al (2015) Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci 18:631–636. https://doi.org/10.1038/nn.4000 CrossRefPubMed

47.

Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA et al (2018) Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of alzheimer’s disease not evident in mouse models. Cell Rep 22:832–847. https://doi.org/10.1016/j.celrep.2017.12.066 CrossRefPubMed

48.

Galli SJ, Borregaard N, Wynn TA (2011) Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol 12:1035–1044. https://doi.org/10.1038/ni.2109 CrossRefPubMedPubMedCentral

49.

Gardner A, Ruffell B (2016) Dendritic cells and cancer immunity. Trends Immunol 37:855–865. https://doi.org/10.1016/j.it.2016.09.006 CrossRefPubMedPubMedCentral

50.

Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PE, Caulfield T et al (2013) Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 126:829–844. https://doi.org/10.1007/s00401-013-1192-8 CrossRefPubMedPubMedCentral

51.

Ghoshal N, Dearborn JT, Wozniak DF, Cairns NJ (2012) Core features of frontotemporal dementia recapitulated in progranulin knockout mice. Neurobiol Dis 45:395–408. https://doi.org/10.1016/j.nbd.2011.08.029 CrossRefPubMed

52.

Gibbons L, Rollinson S, Thompson JC, Robinson A, Davidson YS, Richardson A et al (2015) Plasma levels of progranulin and interleukin-6 in frontotemporal lobar degeneration. Neurobiol Aging 36(1603):e1601–e1604. https://doi.org/10.1016/j.neurobiolaging.2014.10.023 CrossRef

53.

Gibson SB, Abbott D, Farnham JM, Thai KK, McLean H, Figueroa KP et al (2016) Population-based risks for cancer in patients with ALS. Neurology 87:289–294. https://doi.org/10.1212/WNL.0000000000002757 CrossRefPubMedPubMedCentral

54.

Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G et al (2012) A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11:54–65. https://doi.org/10.1016/S1474-4422(11)70261-7 CrossRefPubMed

55.

Ginhoux F, Lim S, Hoeffel G, Low D, Huber T (2013) Origin and differentiation of microglia. Front Cell Neurosci 7:45. https://doi.org/10.3389/fncel.2013.00045 CrossRefPubMedPubMedCentral

56.

Gleason CE, Ordureau A, Gourlay R, Arthur JS, Cohen P (2011) Polyubiquitin binding to optineurin is required for optimal activation of TANK-binding kinase 1 and production of interferon beta. J Biol Chem 286:35663–35674. https://doi.org/10.1074/jbc.M111.267567 CrossRefPubMedPubMedCentral

57.

Goldknopf IL, Sheta EA, Bryson J, Folsom B, Wilson C, Duty J et al (2006) Complement C3c and related protein biomarkers in amyotrophic lateral sclerosis and Parkinson’s disease. Biochem Biophys Res Commun 342:1034–1039. https://doi.org/10.1016/j.bbrc.2006.02.051 CrossRefPubMed

58.

Goldmann T, Wieghofer P, Jordao MJ, Prutek F, Hagemeyer N, Frenzel K et al (2016) Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat Immunol 17:797–805. https://doi.org/10.1038/ni.3423 CrossRefPubMedPubMedCentral

59.

Graves MC, Fiala M, Dinglasan LA, Liu NQ, Sayre J, Chiappelli F et al (2004) Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells. Amyotroph Lateral Scler Motor Neuron Disord 5:213–219CrossRef

60.

Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775CrossRefPubMed

61.

Hall ED, Oostveen JA, Gurney ME (1998) Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23:249–256CrossRefPubMed

62.

Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394. https://doi.org/10.1038/nn1997 CrossRefPubMed

63.

Harms MB, Cady J, Zaidman C, Cooper P, Bali T, Allred P et al (2013) Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis. Neurobiol Aging 34(2234):e2213–e2239. https://doi.org/10.1016/j.neurobiolaging.2013.03.006 CrossRef

64.

Harms MM, Miller TM, Baloh RH (1993) TARDBP-related amyotrophic lateral sclerosis. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews((R)), City

65.

Haverkamp LJ, Appel V, Appel SH (1995) Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction. Brain 118((Pt 3)):707–719CrossRefPubMed

66.

Hawkes CA, McLaurin J (2009) Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc Natl Acad Sci USA 106:1261–1266. https://doi.org/10.1073/pnas.0805453106 CrossRefPubMedPubMedCentral

67.

Heng TS, Painter MW, Immunological Genome Project C (2008) The Immunological Genome Project: networks of gene expression in immune cells. Nat Immunol 9:1091–1094. https://doi.org/10.1038/ni1008-1091 CrossRefPubMed

68.

Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE et al (2013) Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med 5:64–79. https://doi.org/10.1002/emmm.201201544 CrossRefPubMed

69.

Henkel JS, Beers DR, Zhao W, Appel SH (2009) Microglia in ALS: the good, the bad, and the resting. J Neuroimmune Pharmacol 4:389–398. https://doi.org/10.1007/s11481-009-9171-5 CrossRefPubMed

70.

Henkel JS, Engelhardt JI, Siklos L, Simpson EP, Kim SH, Pan T et al (2004) Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol 55:221–235. https://doi.org/10.1002/ana.10805 CrossRefPubMed

71.

Herman M, Ciancanelli M, Ou YH, Lorenzo L, Klaudel-Dreszler M, Pauwels E et al (2012) Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J Exp Med 209:1567–1582. https://doi.org/10.1084/jem.20111316 CrossRefPubMedPubMedCentral

72.

Hong S, Dissing-Olesen L, Stevens B (2016) New insights on the role of microglia in synaptic pruning in health and disease. Curr Opin Neurobiol 36:128–134. https://doi.org/10.1016/j.conb.2015.12.004 CrossRefPubMed

73.

Ismail A, Cooper-Knock J, Highley JR, Milano A, Kirby J, Goodall E et al (2013) Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of C9ORF72. J Neurol Neurosurg Psychiatry 84:79–87. https://doi.org/10.1136/jnnp-2012-303326 CrossRefPubMed

74.

Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y et al (2016) RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science 353:603–608. https://doi.org/10.1126/science.aaf6803 CrossRefPubMedPubMedCentral

75.

Ivashkiv LB, Donlin LT (2014) Regulation of type I interferon responses. Nat Rev Immunol 14:36–49. https://doi.org/10.1038/nri3581 CrossRefPubMedPubMedCentral

76.

Jara JH, Genc B, Stanford MJ, Pytel P, Roos RP, Weintraub S et al (2017) Evidence for an early innate immune response in the motor cortex of ALS. J Neuroinflam 14:129. https://doi.org/10.1186/s12974-017-0896-4 CrossRef

77.

Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ et al (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–864. https://doi.org/10.1016/j.neuron.2010.11.036 CrossRefPubMedPubMedCentral

78.

Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574. https://doi.org/10.1038/ng.132 CrossRefPubMed

79.

Kawamata T, Akiyama H, Yamada T, McGeer PL (1992) Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol 140:691–707PubMedPubMedCentral

80.

Kelemen J, Hedlund W, Orlin JB, Berkman EM, Munsat TL (1983) Plasmapheresis with immunosuppression in amyotrophic lateral sclerosis. Arch Neurol 40:752–753CrossRefPubMed

81.

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK et al (2017) A unique microglia type associated with restricting development of alzheimer’s disease. Cell 169(1276–1290):e1217. https://doi.org/10.1016/j.cell.2017.05.018 CrossRef

82.

Kim WK, Alvarez X, Fisher J, Bronfin B, Westmoreland S, McLaurin J et al (2006) CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. Am J Pathol 168:822–834. https://doi.org/10.2353/ajpath.2006.050215 CrossRefPubMedPubMedCentral

83.

Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318CrossRefPubMed

84.

Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208. https://doi.org/10.1126/science.1166066 CrossRefPubMed

85.

La Spada AR, Taylor JP (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11:247–258. https://doi.org/10.1038/nrg2748 CrossRefPubMedPubMedCentral

86.

Leigh PN, Whitwell H, Garofalo O, Buller J, Swash M, Martin JE et al (1991) Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity. Brain 114((Pt 2)):775–788CrossRefPubMed

87.

Liao B, Zhao W, Beers DR, Henkel JS, Appel SH (2012) Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol 237:147–152. https://doi.org/10.1016/j.expneurol.2012.06.011 CrossRefPubMedPubMedCentral

88.

Lomen-Hoerth C, Anderson T, Miller B (2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59:1077–1079CrossRefPubMed

89.

London A, Cohen M, Schwartz M (2013) Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front Cell Neurosci 7:34. https://doi.org/10.3389/fncel.2013.00034 CrossRefPubMedPubMedCentral

90.

Lu CH, Allen K, Oei F, Leoni E, Kuhle J, Tree T et al (2016) Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis. Neurol Neuroimmunol Neuroinflam 3:e244. https://doi.org/10.1212/NXI.0000000000000244 CrossRef

91.

Lyck L, Santamaria ID, Pakkenberg B, Chemnitz J, Schroder HD, Finsen B et al (2009) An empirical analysis of the precision of estimating the numbers of neurons and glia in human neocortex using a fractionator-design with sub-sampling. J Neurosci Methods 182:143–156. https://doi.org/10.1016/j.jneumeth.2009.06.003 CrossRefPubMed

92.

Mackenzie IR, Arzberger T, Kremmer E, Troost D, Lorenzl S, Mori K et al (2013) Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol 126:859–879. https://doi.org/10.1007/s00401-013-1181-y CrossRefPubMed

93.

Mantovani S, Garbelli S, Pasini A, Alimonti D, Perotti C, Melazzini M et al (2009) Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J Neuroimmunol 210:73–79. https://doi.org/10.1016/j.jneuroim.2009.02.012 CrossRefPubMed

94.

Marchlik E, Thakker P, Carlson T, Jiang Z, Ryan M, Marusic S et al (2010) Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality. J Leukoc Biol 88:1171–1180. https://doi.org/10.1189/jlb.0210071 CrossRefPubMed

95.

Markovinovic A, Cimbro R, Ljutic T, Kriz J, Rogelj B, Munitic I (2017) Optineurin in amyotrophic lateral sclerosis: multifunctional adaptor protein at the crossroads of different neuroprotective mechanisms. Prog Neurobiol 154:1–20. https://doi.org/10.1016/j.pneurobio.2017.04.005 CrossRefPubMed

96.

Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A, Sarrazin S et al (2016) Microglia development follows a stepwise program to regulate brain homeostasis. Science 353:aad8670. https://doi.org/10.1126/science.aad8670 CrossRefPubMed

97.

Mathys H, Adaikkan C, Gao F, Young JZ, Manet E, Hemberg M et al (2017) Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell reports 21:366–380. https://doi.org/10.1016/j.celrep.2017.09.039 CrossRefPubMed

98.

May C, Nordhoff E, Casjens S, Turewicz M, Eisenacher M, Gold R et al (2014) Highly immunoreactive IgG antibodies directed against a set of twenty human proteins in the sera of patients with amyotrophic lateral sclerosis identified by protein array. PLoS One 9:e89596. https://doi.org/10.1371/journal.pone.0089596 CrossRefPubMedPubMedCentral

99.

McCombe PA, Henderson RD (2011) The Role of immune and inflammatory mechanisms in ALS. Curr Mol Med 11:246–254CrossRefPubMedPubMedCentral

100.

McGoldrick P, Zhang M, van Blitterswijk M, Sato C, Moreno D, Xiao S et al (2018) Unaffected mosaic C9orf72 case: RNA foci, dipeptide proteins, but upregulated C9orf72 expression. Neurology 90:e323–e331. https://doi.org/10.1212/WNL.0000000000004865 CrossRefPubMedPubMedCentral

101.

Mehta P, Kaye W, Raymond J, Wu R, Larson T, Punjani R et al (2018) Prevalence of amyotrophic lateral sclerosis—United States, 2014. MMWR Morb Mortal Wkly Rep 67:216–218. https://doi.org/10.15585/mmwr.mm6707a3 CrossRefPubMedPubMedCentral

102.

Meissner F, Molawi K, Zychlinsky A (2010) Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci USA 107:13046–13050. https://doi.org/10.1073/pnas.1002396107 CrossRefPubMedPubMedCentral

103.

Miller ZA, Rankin KP, Graff-Radford NR, Takada LT, Sturm VE, Cleveland CM et al (2013) TDP-43 frontotemporal lobar degeneration and autoimmune disease. J Neurol Neurosurg Psychiatry 84:956–962. https://doi.org/10.1136/jnnp-2012-304644 CrossRefPubMed

104.

Miller ZA, Sturm VE, Camsari GB, Karydas A, Yokoyama JS, Grinberg LT et al (2016) Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts: completing the picture. Neurol (R) Neuroimmunol Neuroinflam 3:e301. https://doi.org/10.1212/NXI.0000000000000301 CrossRef

105.

Monstad I, Dale I, Petlund CF, Sjaastad O (1979) Plasma exchange in motor neuron disease. A controlled study. J Neurol 221:59–66CrossRefPubMed

106.

Munitic I, Giardino Torchia ML, Meena NP, Zhu G, Li CC, Ashwell JD (2013) Optineurin insufficiency impairs IRF3 but not NF-kappaB activation in immune cells. J Immunol 191:6231–6240. https://doi.org/10.4049/jimmunol.1301696 CrossRefPubMed

107.

Murdock BJ, Zhou T, Kashlan SR, Little RJ, Goutman SA, Feldman EL (2017) Correlation of peripheral immunity with rapid amyotrophic lateral sclerosis progression. JAMA Neurol 74:1446–1454. https://doi.org/10.1001/jamaneurol.2017.2255 CrossRefPubMedPubMedCentral

108.

Nataf S, Pays L (2015) Gene co-expression analysis unravels a link between C9orf72 and RNA metabolism in myeloid cells. Acta Neuropathol Commun 3:64. https://doi.org/10.1186/s40478-015-0242-y CrossRefPubMedPubMedCentral

109.

Neumann H, Kotter MR, Franklin RJ (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132:288–295. https://doi.org/10.1093/brain/awn109 CrossRefPubMed

110.

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. https://doi.org/10.1126/science.1134108 CrossRefPubMed

111.

Ng AS, Rademakers R, Miller BL (2015) Frontotemporal dementia: a bridge between dementia and neuromuscular disease. Ann N Y Acad Sci 1338:71–93. https://doi.org/10.1111/nyas.12638 CrossRefPubMed

112.

O’Rourke JG, Bogdanik L, Yanez A, Lall D, Wolf AJ, Muhammad AK et al (2016) C9orf72 is required for proper macrophage and microglial function in mice. Science 351:1324–1329. https://doi.org/10.1126/science.aaf1064 CrossRefPubMedPubMedCentral

113.

Oakes JA, Davies MC, Collins MO (2017) TBK1: a new player in ALS linking autophagy and neuroinflammation. Mol Brain 10:5. https://doi.org/10.1186/s13041-017-0287-x CrossRefPubMedPubMedCentral

114.

Obaid R, Wani SE, Azfer A, Hurd T, Jones R, Cohen P et al (2015) Optineurin negatively regulates osteoclast differentiation by modulating NF-kappaB and interferon signaling: implications for paget’s disease. Cell Rep 13:1096–1102. https://doi.org/10.1016/j.celrep.2015.09.071 CrossRefPubMedPubMedCentral

115.

Olarte MR, Schoenfeldt RS, McKiernan G, Rowland LP (1980) Plasmapheresis in amyotrophic lateral sclerosis. Ann Neurol 8:644–645. https://doi.org/10.1002/ana.410080625 CrossRefPubMed

116.

Pagani MR, Gonzalez LE, Uchitel OD (2011) Autoimmunity in amyotrophic lateral sclerosis: past and present. Neurol Res Int 2011:497080. https://doi.org/10.1155/2011/497080 CrossRefPubMedPubMedCentral

117.

Paolicelli RC, Jawaid A, Henstridge CM, Valeri A, Merlini M, Robinson JL et al (2017) TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron 95(297–308):e296. https://doi.org/10.1016/j.neuron.2017.05.037 CrossRef

118.

Park L, Uekawa K, Garcia-Bonilla L, Koizumi K, Murphy M, Pistik R et al (2017) Brain perivascular macrophages initiate the neurovascular dysfunction of alzheimer abeta peptides. Circ Res 121:258–269. https://doi.org/10.1161/CIRCRESAHA.117.311054 CrossRefPubMedPubMedCentral

119.

Pelvig DP, Pakkenberg H, Stark AK, Pakkenberg B (2008) Neocortical glial cell numbers in human brains. Neurobiol Aging 29:1754–1762. https://doi.org/10.1016/j.neurobiolaging.2007.04.013 CrossRefPubMed

120.

Pestronk A, Adams RN, Cornblath D, Kuncl RW, Drachman DB, Clawson L (1989) Patterns of serum IgM antibodies to GM1 and GD1a gangliosides in amyotrophic lateral sclerosis. Ann Neurol 25:98–102. https://doi.org/10.1002/ana.410250118 CrossRefPubMed

121.

Petkau TL, Kosior N, de Asis K, Connolly C, Leavitt BR (2017) Selective depletion of microglial progranulin in mice is not sufficient to cause neuronal ceroid lipofuscinosis or neuroinflammation. J Neuroinflam 14:225. https://doi.org/10.1186/s12974-017-1000-9 CrossRef

122.

Polfliet MM, van de Veerdonk F, Dopp EA, van Kesteren-Hendrikx EM, van Rooijen N, Dijkstra CD et al (2002) The role of perivascular and meningeal macrophages in experimental allergic encephalomyelitis. J Neuroimmunol 122:1–8CrossRefPubMed

123.

Popovich PG, Hickey WF (2001) Bone marrow chimeric rats reveal the unique distribution of resident and recruited macrophages in the contused rat spinal cord. J Neuropathol Exp Neurol 60:676–685CrossRefPubMed

124.

Pottier C, Bieniek KF, Finch N, van de Vorst M, Baker M, Perkersen R et al (2015) Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta Neuropathol 130:77–92. https://doi.org/10.1007/s00401-015-1436-x CrossRefPubMedPubMedCentral

125.

Pramatarova A, Laganiere J, Roussel J, Brisebois K, Rouleau GA (2001) Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci 21:3369–3374CrossRefPubMedPubMedCentral

126.

Prinz M, Priller J (2017) The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci 20:136–144. https://doi.org/10.1038/nn.4475 CrossRefPubMed

127.

Ransohoff RM (2016) A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19:987–991. https://doi.org/10.1038/nn.4338 CrossRefPubMed

128.

Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268. https://doi.org/10.1016/j.neuron.2011.09.010 CrossRefPubMedPubMedCentral

129.

Rizzu P, Blauwendraat C, Heetveld S, Lynes EM, Castillo-Lizardo M, Dhingra A et al (2016) C9orf72 is differentially expressed in the central nervous system and myeloid cells and consistently reduced in C9orf72, MAPT and GRN mutation carriers. Acta Neuropathol Commun 4:37. https://doi.org/10.1186/s40478-016-0306-7 CrossRefPubMedPubMedCentral

130.

Sakaguchi S, Miyara M, Costantino CM, Hafler DA (2010) FOXP3 + regulatory T cells in the human immune system. Nat Rev Immunol 10:490–500. https://doi.org/10.1038/nri2785 CrossRefPubMed

131.

Sako W, Ito H, Yoshida M, Koizumi H, Kamada M, Fujita K et al (2012) Nuclear factor kappa B expression in patients with sporadic amyotrophic lateral sclerosis and hereditary amyotrophic lateral sclerosis with optineurin mutations. Clin Neuropathol 31:418–423. https://doi.org/10.5414/NP300493 CrossRefPubMed

132.

Sanagi T, Yuasa S, Nakamura Y, Suzuki E, Aoki M, Warita H et al (2010) Appearance of phagocytic microglia adjacent to motoneurons in spinal cord tissue from a presymptomatic transgenic rat model of amyotrophic lateral sclerosis. J Neurosci Res 88:2736–2746. https://doi.org/10.1002/jnr.22424 CrossRefPubMed

133.

Sareen D, O’Rourke JG, Meera P, Muhammad AK, Grant S, Simpkinson M et al (2013) Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 5:208ra149. https://doi.org/10.1126/scitranslmed.3007529 CrossRefPubMedPubMedCentral

134.

Schafer DP, Stevens B (2015) Microglia function in central nervous system development and plasticity. Cold Spring Harbor Perspect Biol 7:a020545. https://doi.org/10.1101/cshperspect.a020545 CrossRef

135.

Sellier C, Campanari ML, Julie Corbier C, Gaucherot A, Kolb-Cheynel I, Oulad-Abdelghani M et al (2016) Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J 35:1276–1297. https://doi.org/10.15252/embj.201593350 CrossRefPubMedPubMedCentral

136.

Sheean RK, McKay FC, Cretney E, Bye CR, Perera ND, Tomas D et al (2018) Association of regulatory T-Cell expansion with progression of amyotrophic lateral sclerosis: a study of humans and a transgenic mouse model. JAMA Neurol 75:681–689. https://doi.org/10.1001/jamaneurol.2018.0035 CrossRefPubMedPubMedCentral

137.

Shi Y, Lin S, Staats KA, Li Y, Chang WH, Hung ST et al (2018) Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med 24:313–325. https://doi.org/10.1038/nm.4490 CrossRefPubMedPubMedCentral

138.

Shy ME, Rowland LP, Smith T, Trojaborg W, Latov N, Sherman W et al (1986) Motor neuron disease and plasma cell dyscrasia. Neurology 36:1429–1436CrossRefPubMed

139.

Sjogren M, Folkesson S, Blennow K, Tarkowski E (2004) Increased intrathecal inflammatory activity in frontotemporal dementia: pathophysiological implications. J Neurol Neurosurg Psychiatry 75:1107–1111. https://doi.org/10.1136/jnnp.2003.019422 CrossRefPubMedPubMedCentral

140.

Slowicka K, Vereecke L, Mc Guire C, Sze M, Maelfait J, Kolpe A et al (2016) Optineurin deficiency in mice is associated with increased sensitivity to Salmonella but does not affect proinflammatory NF-kappaB signaling. Eur J Immunol 46:971–980. https://doi.org/10.1002/eji.201545863 CrossRefPubMed

141.

Spiller KJ, Restrepo CR, Khan T, Dominique MA, Fang TC, Canter RG et al (2018) Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nat Neurosci 21:329–340. https://doi.org/10.1038/s41593-018-0083-7 CrossRefPubMedPubMedCentral

142.

Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672. https://doi.org/10.1126/science.1154584 CrossRefPubMedPubMedCentral

143.

Sudria-Lopez E, Koppers M, de Wit M, van der Meer C, Westeneng HJ, Zundel CA et al (2016) Full ablation of C9orf72 in mice causes immune system-related pathology and neoplastic events but no motor neuron defects. Acta Neuropathol 132:145–147. https://doi.org/10.1007/s00401-016-1581-x CrossRefPubMedPubMedCentral

144.

Sullivan PM, Zhou X, Robins AM, Paushter DH, Kim D, Smolka MB et al (2016) The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Acta Neuropathol Commun 4:51. https://doi.org/10.1186/s40478-016-0324-5 CrossRefPubMedPubMedCentral

145.

Tanishima M, Takashima S, Honda A, Yasuda D, Tanikawa T, Ishii S et al (2017) Identification of optineurin as an interleukin-1 receptor-associated kinase 1-binding protein and its role in regulation of MyD88-dependent signaling. J Biol Chem 292:17250–17257. https://doi.org/10.1074/jbc.M117.813899 CrossRefPubMedPubMedCentral

146.

Therrien M, Rouleau GA, Dion PA, Parker JA (2013) Deletion of C9ORF72 results in motor neuron degeneration and stress sensitivity in C. elegans. PLoS One 8:e83450. https://doi.org/10.1371/journal.pone.0083450 CrossRefPubMedPubMedCentral

147.

Thonhoff JR, Beers DR, Zhao W, Pleitez M, Simpson EP, Berry JD et al (2018) Expanded autologous regulatory T-lymphocyte infusions in ALS: a phase I, first-in-human study. Neurol (R) Neuroimmunol Neuroinflam 5:e465. https://doi.org/10.1212/NXI.0000000000000465 CrossRef

148.

Tocut M, Brenner R, Zandman-Goddard G (2018) Autoimmune phenomena and disease in cancer patients treated with immune checkpoint inhibitors. Autoimmun Rev 17:610–616. https://doi.org/10.1016/j.autrev.2018.01.010 CrossRefPubMed

149.

Town T, Nikolic V, Tan J (2005) The microglial “activation” continuum: from innate to adaptive responses. Journal of neuroinflammation 2:24. https://doi.org/10.1186/1742-2094-2-24 CrossRefPubMedPubMedCentral

150.

Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ et al (2004) Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 15:601–609. https://doi.org/10.1016/j.nbd.2003.12.012 CrossRefPubMed

151.

Turner MR, Goldacre R, Ramagopalan S, Talbot K, Goldacre MJ (2013) Autoimmune disease preceding amyotrophic lateral sclerosis: an epidemiologic study. Neurology 81:1222–1225. https://doi.org/10.1212/WNL.0b013e3182a6cc13 CrossRefPubMedPubMedCentral

152.

Uchitel OD, Appel SH, Crawford F, Sczcupak L (1988) Immunoglobulins from amyotrophic lateral sclerosis patients enhance spontaneous transmitter release from motor-nerve terminals. Proc Natl Acad Sci USA 85:7371–7374CrossRefPubMedPubMedCentral

153.

Van Mossevelde S, van der Zee J, Gijselinck I, Engelborghs S, Sieben A, Van Langenhove T et al (2016) Clinical features of TBK1 carriers compared with C9orf72, GRN and non-mutation carriers in a Belgian cohort. Brain 139:452–467. https://doi.org/10.1093/brain/awv358 CrossRefPubMed

154.

Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211. https://doi.org/10.1126/science.1165942 CrossRefPubMedPubMedCentral

155.

Wang WB, Levy DE, Lee CK (2011) STAT3 negatively regulates type I IFN-mediated antiviral response. J Immunol 187:2578–2585. https://doi.org/10.4049/jimmunol.1004128 CrossRefPubMed

156.

Weydt P, Yuen EC, Ransom BR, Moller T (2004) Increased cytotoxic potential of microglia from ALS-transgenic mice. Glia 48:179–182. https://doi.org/10.1002/glia.20062 CrossRefPubMed

157.

Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA et al (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14:1105–1116CrossRefPubMed

158.

Wood H (2011) A hexanucleotide repeat expansion in C9ORF72 links amyotrophic lateral sclerosis and frontotemporal dementia. Nature Rev Neurol 7:595. https://doi.org/10.1038/nrneurol.2011.162 CrossRef

159.

Worbs T, Hammerschmidt SI, Forster R (2017) Dendritic cell migration in health and disease. Nat Rev Immunol 17:30–48. https://doi.org/10.1038/nri.2016.116 CrossRefPubMed

160.

Xiao Q, Zhao W, Beers DR, Yen AA, Xie W, Henkel JS et al (2007) Mutant SOD1(G93A) microglia are more neurotoxic relative to wild-type microglia. J Neurochem 102:2008–2019. https://doi.org/10.1111/j.1471-4159.2007.04677.x CrossRefPubMed

161.

Xiao Y, Zou Q, Xie X, Liu T, Li HS, Jie Z et al (2017) The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity. J Exp Med 214:1493–1507. https://doi.org/10.1084/jem.20161524 CrossRefPubMedPubMedCentral

162.

Yamanaka K, Boillee S, Roberts EA, Garcia ML, McAlonis-Downes M, Mikse OR et al (2008) Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc Natl Acad Sci USA 105:7594–7599. https://doi.org/10.1073/pnas.0802556105 CrossRefPubMedPubMedCentral

163.

Yi FH, Lautrette C, Vermot-Desroches C, Bordessoule D, Couratier P, Wijdenes J et al (2000) In vitro induction of neuronal apoptosis by anti-Fas antibody-containing sera from amyotrophic lateral sclerosis patients. J Neuroimmunol 109:211–220CrossRefPubMed

164.

Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T et al (2010) Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med 207:117–128. https://doi.org/10.1084/jem.20091568 CrossRefPubMedPubMedCentral

165.

Yu J, Zhou X, Chang M, Nakaya M, Chang JH, Xiao Y et al (2015) Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation. Nature Commun 6:6074. https://doi.org/10.1038/ncomms7074 CrossRef

166.

Zhang R, Gascon R, Miller RG, Gelinas DF, Mass J, Hadlock K et al (2005) Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol 159:215–224. https://doi.org/10.1016/j.jneuroim.2004.10.009 CrossRefPubMed

167.

Zhang R, Hadlock KG, Do H, Yu S, Honrada R, Champion S et al (2011) Gene expression profiling in peripheral blood mononuclear cells from patients with sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol 230:114–123. https://doi.org/10.1016/j.jneuroim.2010.08.012 CrossRefPubMed

168.

Zhao W, Beers DR, Henkel JS, Zhang W, Urushitani M, Julien JP et al (2010) Extracellular mutant SOD1 induces microglial-mediated motoneuron injury. Glia 58:231–243. https://doi.org/10.1002/glia.20919 CrossRefPubMedPubMedCentral

169.

Zhao W, Beers DR, Liao B, Henkel JS, Appel SH (2012) Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiol Dis 48:418–428. https://doi.org/10.1016/j.nbd.2012.07.008 CrossRefPubMedPubMedCentral

170.

Zhao W, Xie W, Le W, Beers DR, He Y, Henkel JS et al (2004) Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism. J Neuropathol Exp Neurol 63:964–977CrossRefPubMed

171.

Zondler L, Muller K, Khalaji S, Bliederhauser C, Ruf WP, Grozdanov V et al (2016) Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol 132:391–411. https://doi.org/10.1007/s00401-016-1548-y CrossRefPubMed

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Inflammation in ALS/FTD pathogenesis

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2019

The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis

Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA

Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology

Neuroinflammation, the thread connecting neurological disease

Beta-amyloid pathology in human brain microvessel extracts from the parietal cortex: relation with cerebral amyloid angiopathy and Alzheimer’s disease

The complexity of neuroinflammation consequent to traumatic brain injury: from research evidence to potential treatments