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Differential contribution of microglia and monocytes in neurodegenerative diseases

  • High Impact Review in Neuroscience, Neurology or Psychiatry - Review Article
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Abstract

Neuroinflammation is a hallmark of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Microglia, the innate immune cells of the CNS, are the first to react to pathological insults. However, multiple studies have also demonstrated an involvement of peripheral monocytes in several neurodegenerative diseases. Due to the different origins of these two cell types, it is important to distinguish their role and function in the development and progression of these diseases. In this review, we will summarize and discuss the current knowledge of the differential contributions of microglia and monocytes in the common neurodegenerative diseases AD, PD, and ALS, as well as multiple sclerosis, which is now regarded as a combination of inflammatory processes and neurodegeneration. Until recently, it has been challenging to differentiate microglia from monocytes, as there were no specific markers. Therefore, the recent identification of specific molecular signatures of both cell types will help to advance our understanding of their differential contribution in neurodegenerative diseases.

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References

  • Aharoni R (2013) New findings and old controversies in the research of multiple sclerosis and its model experimental autoimmune encephalomyelitis. Expert Rev Clin Immunol 9(5):423–440

    Article  CAS  PubMed  Google Scholar 

  • 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(12):1538–1543

    Article  CAS  PubMed  Google Scholar 

  • 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(9):1142–1149

    Article  CAS  PubMed  Google Scholar 

  • Alexianu ME, Kozovska M, Appel SH (2001) Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57(7):1282–1289

    Article  CAS  PubMed  Google Scholar 

  • Appel SH, Smith RG, Engelhardt JI, Stefani E (1993) Evidence for autoimmunity in amyotrophic lateral sclerosis. J Neurol Sci 118(2):169–174

    Article  CAS  PubMed  Google Scholar 

  • Appel SH, Zhao W, Beers DR, Henkel JS (2011) The microglial-motoneuron dialogue in ALS. Acta Myol 30(1):4–8

    CAS  PubMed  PubMed Central  Google Scholar 

  • Asai H, Ikezu S, Woodbury ME, Yonemoto GM, Cui L, Ikezu T (2014) Accelerated neurodegeneration and neuroinflammation in transgenic mice expressing P301L tau mutant and tau-tubulin kinase 1. Am J Pathol 184(3):808–818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kugler S, Ikezu T (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18(11):1584–1593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C, Zheng H, Li X, Rademakers R, Kang SS, Xu H, Younkin S, Das P, Fryer JD, Bu G (2015) Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J Biol Chem 290(43):26043–26050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Atanasio A, Decman V, White D, Ramos M, Ikiz B, Lee HC, Siao CJ, Brydges S, LaRosa E, Bai Y, Fury W, Burfeind P, Zamfirova R, Warshaw G, Orengo J, Oyejide A, Fralish M, Auerbach W, Poueymirou W, Freudenberg J, Gong G, Zambrowicz B, Valenzuela D, Yancopoulos G, Murphy A, Thurston G, Lai KM (2016) C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci Rep 6:23204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, Sarnacki S, Cumano A, Lauvau G, Geissmann F (2007) Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317(5838):666–670

    Article  CAS  PubMed  Google Scholar 

  • Bartels AL, Willemsen AT, Doorduin J, de Vries EF, Dierckx RA, Leenders KL (2010) [11C]-PK11195 PET: quantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinson’s disease? Parkinsonism Relat Disord 16(1):57–59

    Article  CAS  PubMed  Google Scholar 

  • Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, Mulinyawe SB, Bohlen CJ, Adil A, Tucker A, Weissman IL, Chang EF, Li G, Grant GA, Hayden Gephart MG, Barres BA (2016) New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci USA 113(12):E1738–1746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biju K, Zhou Q, Li G, Imam SZ, Roberts JL, Morgan WW, Clark RA, Li S (2010) Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration: a therapeutic strategy for Parkinson’s disease. Mol Ther 18(8):1536–1544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blesa J, Przedborski S (2014) Parkinson’s disease: animal models and dopaminergic cell vulnerability. Front Neuroanat 8:155

    Article  PubMed  PubMed Central  Google Scholar 

  • Bliederhaeuser C, Zondler L, Grozdanov V, Ruf WP, Brenner D, Melrose HL, Bauer P, Ludolph AC, Gillardon F, Kassubek J, Weishaupt JH, Danzer KM (2016) LRRK2 contributes to monocyte dysregulation in Parkinson’s disease. Acta Neuropathol Commun 4(1):123

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bodea LG, Wang Y, Linnartz-Gerlach B, Kopatz J, Sinkkonen L, Musgrove R, Kaoma T, Muller A, Vallar L, Di Monte DA, Balling R, Neumann H (2014) Neurodegeneration by activation of the microglial complement-phagosome pathway. J Neurosci 34(25):8546–8556

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312(5778):1389–1392

    Article  CAS  PubMed  Google Scholar 

  • Boven LA, Van Meurs M, Van Zwam M, Wierenga-Wolf A, Hintzen RQ, Boot RG, Aerts JM, Amor S, Nieuwenhuis EE, Laman JD (2006) Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. Brain 129(Pt 2):517–526

    Article  PubMed  Google Scholar 

  • Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A, Rosenkrantz LL, Imboywa S, Lee M, Von Korff A, I. Alzheimer Disease Neuroimaging, Morris MC, Evans DA, Johnson K, Sperling RA, Schneider JA, Bennett DA, De Jager PL (2013a) CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci 16(7):848–850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A, Rosenkrantz LL, Imboywa S, Lee M, Von Korff A, Morris MC, Evans DA, Johnson K, Sperling RA, Schneider JA, Bennett DA, De Jager PL, Jager PLD (2013b) CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci 16:848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brodacki B, Staszewski J, Toczylowska B, Kozlowska E, Drela N, Chalimoniuk M, Stepien A (2008) Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci Lett 441(2):158–162

    Article  CAS  PubMed  Google Scholar 

  • Brosseron F, Krauthausen M, Kummer M, Heneka MT (2014) Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview. Mol Neurobiol 50:534–544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruck W, Porada P, Poser S, Rieckmann P, Hanefeld F, Kretzschmar HA, Lassmann H (1995) Monocyte/macrophage differentiation in early multiple sclerosis lesions. Ann Neurol 38(5):788–796

    Article  CAS  PubMed  Google Scholar 

  • Burberry A, Suzuki N, Wang JY, Moccia R, Mordes DA, Stewart MH, Suzuki-Uematsu S, Ghosh S, Singh A, Merkle FT, Koszka K, Li QZ, Zon L, Rossi DJ, Trowbridge JJ, Notarangelo LD, Eggan K (2016) Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci Transl Med 8(347):347ra393

    Article  CAS  Google Scholar 

  • Butovsky O, Landa G, Kunis G, Ziv Y, Avidan H, Greenberg N, Schwartz A, Smirnov I, Pollack A, Jung S, Schwartz M (2006a) Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Investig 116(4):905–915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M (2006b) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31(1):149–160

    Article  CAS  PubMed  Google Scholar 

  • Butovsky O, Siddiqui S, Gabriely G, Lanser AJ, Dake B, Murugaiyan G, Doykan CE, Wu PM, Gali RR, Iyer LK, Lawson R, Berry J, Krichevsky AM, Cudkowicz ME, Weiner HL (2012) Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Investig 122(9):3063–3087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17(1):131–143

    Article  CAS  PubMed  Google Scholar 

  • Butovsky O, Jedrychowski MP, Cialic R, Krasemann S, Murugaiyan G, Fanek Z, Greco DJ, Wu PM, Doykan CE, Kiner O, Lawson RJ, Frosch MP, Pochet N, Fatimy RE, Krichevsky AM, Gygi SP, Lassmann H, Berry J, Cudkowicz ME, Weiner HL (2015) Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol 77(1):75–99

    Article  CAS  PubMed  Google Scholar 

  • Buttgereit A, Lelios I, Yu X, Vrohlings M, Krakoski NR, Gautier EL, Nishinakamura R, Becher B, Greter M (2016) Sall1 is a transcriptional regulator defining microglia identity and function. Nat Immunol 17(12):1397–1406

    Article  CAS  PubMed  Google Scholar 

  • Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R, Yuede CM, Galimberti D, Olivecrona G, Klein RS, Cross AH, Otero K, Piccio L (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129(3):429–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924

    Article  CAS  PubMed  Google Scholar 

  • Cardona AE, Sasse ME, Liu L, Cardona SM, Mizutani M, Savarin C, Hu T, Ransohoff RM (2008) Scavenging roles of chemokine receptors: chemokine receptor deficiency is associated with increased levels of ligand in circulation and tissues. Blood 112(2):256–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carlin LM, Stamatiades EG, Auffray C, Hanna RN, Glover L, Vizcay-Barrena G, Hedrick CC, Cook HT, Diebold S, Geissmann F (2013) Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell 153(2):362–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carvey PM, Hendey B, Monahan AJ (2009) The blood–brain barrier in neurodegenerative disease: a rhetorical perspective. J Neurochem 111(2):291–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, Zubair AC, Dickson D, Golde TE, Das P (2010) Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J 24(2):548–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan G, White CC, Winn PA, Cimpean M, Replogle JM, Glick LR, Cuerdon NE, Ryan KJ, Johnson KA, Schneider JA, Bennett DA, Chibnik LB, Sperling RA, Bradshaw EM, De Jager PL (2015) CD33 modulates TREM2: convergence of Alzheimer loci. Nat Neurosci 18(11):1556–1558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaudhuri A (2013) Multiple sclerosis is primarily a neurodegenerative disease. J Neural Transm (Vienna) 120(10):1463–1466

    Article  CAS  Google Scholar 

  • Chiu IM, Phatnani H, Kuligowski M, Tapia JC, Carrasco MA, Zhang M, Maniatis T, Carroll MC (2009) Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc Natl Acad Sci USA 106(49):20960–20965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O’Keeffe S, Phatnani HP, Muratet M, Carroll MC, Levy S, Tavazoie S, Myers RM, Maniatis T (2013) A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep 4(2):385–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, McMahon AP, Doucette W, Siwek D, Ferrante RJ, Brown RH Jr, Julien JP, Goldstein LS, Cleveland DW (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302(5642):113–117

    Article  CAS  PubMed  Google Scholar 

  • Compston A, Coles A (2002) Multiple sclerosis. Lancet 359(9313):1221–1231

    Article  PubMed  Google Scholar 

  • Cook DA, Kannarkat GT, Cintron AF, Butkovich LM, Fraser KB, Chang J, Grigoryan N, Factor SA, West AB, Boss JM, Tansey MG (2017) LRRK2 levels in immune cells are increased in Parkinson’s disease. NPJ Parkinsons Dis 3:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123):921–923

    Article  CAS  PubMed  Google Scholar 

  • Croxford AL, Lanzinger M, Hartmann FJ, Schreiner B, Mair F, Pelczar P, Clausen BE, Jung S, Greter M, Becher B (2015) The cytokine GM-CSF drives the inflammatory signature of CCR2 + monocytes and licenses autoimmunity. Immunity 43(3):502–514

    Article  CAS  PubMed  Google Scholar 

  • Czlonkowska A, Kohutnicka M, Kurkowska-Jastrzebska I, Czlonkowski A (1996) Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson’s disease mice model. Neurodegeneration 5(2):137–143

    Article  CAS  PubMed  Google Scholar 

  • Dagher NN, Najafi AR, Kayala KM, Elmore MR, White TE, Medeiros R, West BL, Green KN (2015) Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J Neuroinflammation 12:139

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909

    Article  CAS  PubMed  Google Scholar 

  • De Groot CJ, Bergers E, Kamphorst W, Ravid R, Polman CH, Barkhof F, van der Valk P (2001) Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions. Brain 124(Pt 8):1635–1645

    Article  PubMed  Google Scholar 

  • DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(2):245–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Depboylu C, Stricker S, Ghobril JP, Oertel WH, Priller J, Hoglinger GU (2012) Brain-resident microglia predominate over infiltrating myeloid cells in activation, phagocytosis and interaction with T-lymphocytes in the MPTP mouse model of Parkinson disease. Exp Neurol 238(2):183–191

    Article  CAS  PubMed  Google Scholar 

  • Elliott JL (2001) Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis. Brain Res Mol Brain Res 95(1–2):172–178

    Article  CAS  PubMed  Google Scholar 

  • Engelhardt JI, Appel SH (1990) IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis. Arch Neurol 47(11):1210–1216

    Article  CAS  PubMed  Google Scholar 

  • Engelhardt JI, Tajti J, Appel SH (1993) Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch Neurol 50(1):30–36

    Article  CAS  PubMed  Google Scholar 

  • Evans MC, Couch Y, Sibson N, Turner MR (2013) Inflammation and neurovascular changes in amyotrophic lateral sclerosis. Mol Cell Neurosci 53:34–41

    Article  CAS  PubMed  Google Scholar 

  • Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120(Pt 3):393–399

    Article  PubMed  Google Scholar 

  • Ford AL, Goodsall AL, Hickey WF, Sedgwick JD (1995) Normal adult ramified microglia separated from other central nervous system macrophages by flow cytometric sorting. Phenotypic differences defined and direct ex vivo antigen presentation to myelin basic protein-reactive CD4+ T cells compared. J Immunol 154(9):4309–4321

    CAS  PubMed  Google Scholar 

  • Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, Ladner KJ, Bevan AK, Foust KD, Godbout JP, Popovich PG, Guttridge DC, Kaspar BK (2014) Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis. Neuron 81(5):1009–1023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia JA, Pino PA, Mizutani M, Cardona SM, Charo IF, Ransohoff RM, Forsthuber TG, Cardona AE (2013) Regulation of adaptive immunity by the fractalkine receptor during autoimmune inflammation. J Immunol 191(3):1063–1072

    Article  CAS  PubMed  Google Scholar 

  • Gardet A, Benita Y, Li C, Sands BE, Ballester I, Stevens C, Korzenik JR, Rioux JD, Daly MJ, Xavier RJ, Podolsky DK (2010) LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol 185(9):5577–5585

    Article  CAS  PubMed  Google Scholar 

  • Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S, Mazloom AR, Ma’ayan A, Chua WJ, Hansen TH, Turley SJ, Merad M, Randolph GJ, Immunological Genome C (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13(11):1118–1128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19(1):71–82

    Article  CAS  PubMed  Google Scholar 

  • Geissmann F, Auffray C, Palframan R, Wirrig C, Ciocca A, Campisi L, Narni-Mancinelli E, Lauvau G (2008) Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses. Immunol Cell Biol 86(5):398–408

    Article  CAS  PubMed  Google Scholar 

  • Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327(5966):656–661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerber YN, Sabourin JC, Rabano M, Vivanco M, Perrin FE (2012) Early functional deficit and microglial disturbances in a mouse model of amyotrophic lateral sclerosis. PLoS One 7(4):e36000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, Eggert K, Oertel W, Banati RB, Brooks DJ (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 21(2):404–412

    Article  CAS  PubMed  Google Scholar 

  • Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140(6):918–934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349(6311):704–706

    Article  CAS  PubMed  Google Scholar 

  • Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129(Pt 8):1953–1971

    Article  PubMed  Google Scholar 

  • Goldmann T, Wieghofer P, Muller PF, Wolf Y, Varol D, Yona S, Brendecke SM, Kierdorf K, Staszewski O, Datta M, Luedde T, Heikenwalder M, Jung S, Prinz M (2013) A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci 16(11):1618–1626

    Article  CAS  PubMed  Google Scholar 

  • Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5(12):953–964

    Article  CAS  PubMed  Google Scholar 

  • Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, Stender JD, Chun HB, Garner H, Geissmann F, Glass CK (2014) Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159(6):1327–1340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gosselin D, Skola D, Coufal NG, Holtman IR, Schlachetzki JCM, Sajti E, Jaeger BN, O’Connor C, Fitzpatrick C, Pasillas MP, Pena M, Adair A, Gonda DD, Levy ML, Ransohoff RM, Gage FH, Glass CK (2017) An environment-dependent transcriptional network specifies human microglia identity. Science 356(6344):eaal3222

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gowing G, Lalancette-Hebert M, Audet JN, Dequen F, Julien JP (2009) Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase. Exp Neurol 220(2):267–275

    Article  CAS  PubMed  Google Scholar 

  • Graber DJ, Hickey WF, Harris BT (2010) Progressive changes in microglia and macrophages in spinal cord and peripheral nerve in the transgenic rat model of amyotrophic lateral sclerosis. J Neuroinflammation 7:8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grathwohl SA, Kalin RE, Bolmont T, Prokop S, Winkelmann G, Kaeser SA, Odenthal J, Radde R, Eldh T, Gandy S, Aguzzi A, Staufenbiel M, Mathews PM, Wolburg H, Heppner FL, Jucker M (2009) Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neurosci 12(11):1361–1363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gravel M, Beland LC, Soucy G, Abdelhamid E, Rahimian R, Gravel C, Kriz J (2016) IL-10 controls early microglial phenotypes and disease onset in ALS caused by misfolded superoxide dismutase 1. J Neurosci 36(3):1031–1048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenhalgh AD, Passos Dos Santos R, Zarruk JG, Salmon CK, Kroner A, David S (2016) Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease. Brain Behav Immun 56:61–67

    Article  CAS  PubMed  Google Scholar 

  • Greter M, Lelios I, Croxford AL (2015) Microglia versus myeloid cell nomenclature during brain inflammation. Front Immunol 6:249

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, Hooli B, Choi SH, Hyman BT, Tanzi RE (2013) Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78(4):631–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grozdanov V, Bliederhaeuser C, Ruf WP, Roth V, Fundel-Clemens K, Zondler L, Brenner D, Martin-Villalba A, Hengerer B, Kassubek J, Ludolph AC, Weishaupt JH, Danzer KM (2014) Inflammatory dysregulation of blood monocytes in Parkinson’s disease patients. Acta Neuropathol 128(5):651–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JSK, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert J-C, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St P, George-Hyslop A Singleton, Hardy J (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368:117–127

    Article  CAS  PubMed  Google Scholar 

  • Guillot-Sestier MV, Doty KR, Gate D, Rodriguez J Jr, Leung BP, Rezai-Zadeh K, Town T (2015) Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 85(3):534–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haines JD, Inglese M, Casaccia P (2011) Axonal damage in multiple sclerosis. Mt Sinai J Med 78(2):231–243

    Article  PubMed  PubMed Central  Google Scholar 

  • Hakimi M, Selvanantham T, Swinton E, Padmore RF, Tong Y, Kabbach G, Venderova K, Girardin SE, Bulman DE, Scherzer CR, LaVoie MJ, Gris D, Park DS, Angel JB, Shen J, Philpott DJ, Schlossmacher MG (2011) Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J Neural Transm (Vienna) 118(5):795–808

    Article  CAS  Google Scholar 

  • 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(3):249–256

    Article  CAS  PubMed  Google Scholar 

  • Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 42(9):781–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harraz MM, Marden JJ, Zhou W, Zhang Y, Williams A, Sharov VS, Nelson K, Luo M, Paulson H, Schoneich C, Engelhardt JF (2008) SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Investig 118(2):659–670

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, Greter M, Mortha A, Boyer SW, Forsberg EC, Tanaka M, van Rooijen N, Garcia-Sastre A, Stanley ER, Ginhoux F, Frenette PS, Merad M (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38(4):792–804

    Article  CAS  PubMed  Google Scholar 

  • Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9(12):1512–1519

    Article  CAS  PubMed  Google Scholar 

  • Henderson AP, Barnett MH, Parratt JD, Prineas JW (2009) Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann Neurol 66(6):739–753

    Article  PubMed  Google Scholar 

  • Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493(7434):674–678

    Article  CAS  PubMed  Google Scholar 

  • Henkel JS, Engelhardt JI, Siklos L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH (2004) Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol 55(2):221–235

    Article  CAS  PubMed  Google Scholar 

  • Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hovelmeyer N, Waisman A, Rulicke T, Prinz M, Priller J, Becher B, Aguzzi A (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11(2):146–152

    Article  CAS  PubMed  Google Scholar 

  • Heppner FL, Ransohoff RM, Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16(6):358–372

    Article  CAS  PubMed  Google Scholar 

  • Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, El Khoury J (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16(12):1896–1905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoenen C, Gustin A, Birck C, Kirchmeyer M, Beaume N, Felten P, Grandbarbe L, Heuschling P, Heurtaux T (2016) Alpha-synuclein proteins promote pro-inflammatory cascades in microglia: stronger effects of the A53T mutant. PLoS One 11(9):e0162717

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hohsfield LA, Humpel C (2015) Intravenous infusion of monocytes isolated from 2-week-old mice enhances clearance of beta-amyloid plaques in an Alzheimer mouse model. PLoS One 10:1–18

    Article  CAS  Google Scholar 

  • Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, Wes PD, Moller T, Orre M, Kamphuis W, Hol EM, Boddeke EW, Eggen BJ (2015) Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun 3:31

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352(6286):712–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hongge L, Kexin G, Xiaojie M, Nian X, Jinsha H (2015) The role of LRRK2 in the regulation of monocyte adhesion to endothelial cells. J Mol Neurosci 55(1):233–239

    Article  PubMed  CAS  Google Scholar 

  • Hooten KG, Beers DR, Zhao W, Appel SH (2015) Protective and toxic neuroinflammation in amyotrophic lateral sclerosis. Neurotherapeutics 12(2):364–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hornykiewicz O, Kish SJ (1987) Biochemical pathophysiology of Parkinson’s disease. Adv Neurol 45:19–34

    CAS  PubMed  Google Scholar 

  • Huang WX, Huang P, Hillert J (2004) Increased expression of caspase-1 and interleukin-18 in peripheral blood mononuclear cells in patients with multiple sclerosis. Mult Scler 10(5):482–487

    Article  CAS  PubMed  Google Scholar 

  • Huizinga R, van der Star BJ, Kipp M, Jong R, Gerritsen W, Clarner T, Puentes F, Dijkstra CD, van der Valk P, Amor S (2012) Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis. Glia 60(3):422–431

    Article  PubMed  Google Scholar 

  • Imamura K, Suzumura A, Hayashi F, Marunouchi T (1993) Cytokine production by peripheral blood monocytes/macrophages in multiple sclerosis patients. Acta Neurol Scand 87(4):281–285

    Article  CAS  PubMed  Google Scholar 

  • Ingersoll MA, Spanbroek R, Lottaz C, Gautier EL, Frankenberger M, Hoffmann R, Lang R, Haniffa M, Collin M, Tacke F, Habenicht AJ, Ziegler-Heitbrock L, Randolph GJ (2010) Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 115(3):e10–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, Xu G, Margevicius D, Karlo JC, Sousa GL, Cotleur AC, Butovsky O, Bekris L, Staugaitis SM, Leverenz JB, Pimplikar SW, Landreth GE, Howell GR, Ransohoff RM, Lamb BT (2015) TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med 212(3):287–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, Ransohoff RM, Lamb BT, Landreth GE (2017) Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J Neurosci 37(3):637–647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368:107–116

    Article  CAS  PubMed  Google Scholar 

  • Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, Littman DR (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20(11):4106–4114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalkonde YV, Morgan WW, Sigala J, Maffi SK, Condello C, Kuziel W, Ahuja SS, Ahuja SK (2007) Chemokines in the MPTP model of Parkinson’s disease: absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration. Brain Res 1128(1):1–11

    Article  CAS  PubMed  Google Scholar 

  • Kallaur AP, Oliveira SR, Colado Simao AN, Delicatode Almeida ER, Kaminami Morimoto H, Lopes J, de Carvalho Jennings Pereira WL, Marques Andrade R, Muliterno Pelegrino L, Donizete Borelli S, Kaimen-Maciel DR, Reiche EM (2013) Cytokine profile in relapsing-remitting multiple sclerosis patients and the association between progression and activity of the disease. Mol Med Rep 7(3):1010–1020

    Article  CAS  PubMed  Google Scholar 

  • Kawachi I, Lassmann H (2017) Neurodegeneration in multiple sclerosis and neuromyelitis optica. J Neurol Neurosurg Psychiatry 88(2):137–145

    Article  PubMed  Google Scholar 

  • Kawamata T, Akiyama H, Yamada T, McGeer PL (1992) Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol 140(3):691–707

    CAS  PubMed  PubMed Central  Google Scholar 

  • Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169(7):1276–1290 e1217

    Article  CAS  PubMed  Google Scholar 

  • King IL, Dickendesher TL, Segal BM (2009) Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113(14):3190–3197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, Hirakawa A, Takeuchi H, Suzumura A, Ishiguro N, Kadomatsu K (2013) Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis 4:e525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, Miller KR, Prokop S, Kettenmann H, Heppner FL (2013) Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One 8(4):e60921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, O’Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Conde-Sanroman P, Garcias M, Weng Z, Chen H, Tjon E, Mazaheri F, Zrzavy T, Hartman K, Glatzel M, Worthmann A, Lemere CA, Ikezu T, Heppner FL, Lassmann H, Weiner HL, Litvak V, Ochando J, Haass C, Butovsky O (2017) The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47:566–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lampe JB, Gossrau G, Kempe A, Fussel M, Schwurack K, Schroder R, Krause S, Kohnen R, Walter MC, Reichmann H, Lochmuller H (2003) Analysis of HLA class I and II alleles in sporadic inclusion-body myositis. J Neurol 250(11):1313–1317

    Article  PubMed  Google Scholar 

  • Lampron A, Larochelle A, Laflamme N, Prefontaine P, Plante MM, Sanchez MG, Yong VW, Stys PK, Tremblay ME, Rivest S (2015) Inefficient clearance of myelin debris by microglia impairs remyelinating processes. J Exp Med 212(4):481–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lassmann H (2014) Mechanisms of white matter damage in multiple sclerosis. Glia 62(11):1816–1830

    Article  PubMed  Google Scholar 

  • Lassmann H, Bruck W, Lucchinetti CF (2007) The immunopathology of multiple sclerosis: an overview. Brain Pathol 17(2):210–218

    Article  PubMed  PubMed Central  Google Scholar 

  • Lassmann H, van Horssen J, Mahad D (2012) Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 8(11):647–656

    Article  CAS  PubMed  Google Scholar 

  • Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, Jung S, Amit I (2014) Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159(6):1312–1326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lebson L, Nash K, Kamath S, Herber D, Carty N, Lee DC, Li Q, Szekeres K, Jinwal U, Koren J, Dickey CA, Gottschall PE, Morgan D, Gordon MN (2010) Trafficking CD11b-positive blood cells deliver therapeutic genes to the brain of amyloid-depositing transgenic mice. J Neurosci 30:9651–9658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lerman BJ, Hoffman EP, Sutherland ML, Bouri K, Hsu DK, Liu FT, Rothstein JD, Knoblach SM (2012) Deletion of galectin-3 exacerbates microglial activation and accelerates disease progression and demise in a SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Brain Behav 2(5):563–575

    Article  PubMed  PubMed Central  Google Scholar 

  • 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(1):147–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lincecum JM, Vieira FG, Wang MZ, Thompson K, De Zutter GS, Kidd J, Moreno A, Sanchez R, Carrion IJ, Levine BA, Al-Nakhala BM, Sullivan SM, Gill A, Perrin S (2010) From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis. Nat Genet 42(5):392–399

    Article  CAS  PubMed  Google Scholar 

  • Lino MM, Schneider C, Caroni P (2002) Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J Neurosci 22(12):4825–4832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47(6):707–717

    Article  CAS  PubMed  Google Scholar 

  • Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA (2008) Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 28(25):6333–6341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mantovani S, Garbelli S, Pasini A, Alimonti D, Perotti C, Melazzini M, Bendotti C, Mora G (2009) Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J Neuroimmunol 210(1–2):73–79

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Muriana A, Mancuso R, Francos-Quijorna I, Olmos-Alonso A, Osta R, Perry VH, Navarro X, Gomez-Nicola D, Lopez-Vales R (2016) CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves. Sci Rep 6:25663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A, Sarrazin S, Ben-Yehuda H, David E, Zelada Gonzalez F, Perrin P, Keren-Shaul H, Gury M, Lara-Astaiso D, Thaiss CA, Cohen M, Bahar Halpern K, Baruch K, Deczkowska A, Lorenzo-Vivas E, Itzkovitz S, Elinav E, Sieweke MH, Schwartz M, Amit I (2016) Microglia development follows a stepwise program to regulate brain homeostasis. Science 353(6301):aad8670

    Article  PubMed  CAS  Google Scholar 

  • McGeer PL, McGeer EG (2002) Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 26(4):459–470

    Article  CAS  PubMed  Google Scholar 

  • McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38(8):1285–1291

    Article  CAS  PubMed  Google Scholar 

  • McGeer PL, McGeer EG, Kawamata T, Yamada T, Akiyama H (1991) Reactions of the immune system in chronic degenerative neurological diseases. Can J Neurol Sci 18(3 Suppl):376–379

    Article  CAS  PubMed  Google Scholar 

  • Meissner F, Molawi K, Zychlinsky A (2010) Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci USA 107(29):13046–13050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michaud JP, Bellavance MA, Préfontaine P, Rivest S (2013) Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep 5:646–653

    Article  CAS  PubMed  Google Scholar 

  • Mikita J, Dubourdieu-Cassagno N, Deloire MS, Vekris A, Biran M, Raffard G, Brochet B, Canron MH, Franconi JM, Boiziau C, Petry KG (2011) Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration. Mult Scler 17(1):2–15

    Article  CAS  PubMed  Google Scholar 

  • Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W, Priller J, Prinz M (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10(12):1544–1553

    Article  CAS  PubMed  Google Scholar 

  • Mildner A, Mack M, Schmidt H, Bruck W, Djukic M, Zabel MD, Hille A, Priller J, Prinz M (2009) CCR2+ Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132(Pt 9):2487–2500

    Article  PubMed  Google Scholar 

  • Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJM, Ffrench-Constant C (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16(9):1211–1218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitchell RM, Freeman WM, Randazzo WT, Stephens HE, Beard JL, Simmons Z, Connor JR (2009) A CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis. Neurology 72(1):14–19

    Article  CAS  PubMed  Google Scholar 

  • Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, Nagatsu T (1994a) Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett 180(2):147–150

    Article  CAS  PubMed  Google Scholar 

  • Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T (1994b) Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett 165(1–2):208–210

    Article  CAS  PubMed  Google Scholar 

  • Murdock BJ, Bender DE, Segal BM, Feldman EL (2015) The dual roles of immunity in ALS: injury overrides protection. Neurobiol Dis 77:1–12

    Article  CAS  PubMed  Google Scholar 

  • Murdock BJ, Bender DE, Kashlan SR, Figueroa-Romero C, Backus C, Callaghan BC, Goutman SA, Feldman EL (2016) Increased ratio of circulating neutrophils to monocytes in amyotrophic lateral sclerosis. Neurology Neuroimmunol Neuroinflammation 3(4):e242

    Article  Google Scholar 

  • Musaro A (2010) State of the art and the dark side of amyotrophic lateral sclerosis. World J Biol Chem 1(5):62–68

    Article  PubMed  PubMed Central  Google Scholar 

  • Nagata T, Nagano I, Shiote M, Narai H, Murakami T, Hayashi T, Shoji M, Abe K (2007) Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients. Neurol Res 29(8):772–776

    Article  CAS  PubMed  Google Scholar 

  • Nardo G, Pozzi S, Pignataro M, Lauranzano E, Spano G, Garbelli S, Mantovani S, Marinou K, Papetti L, Monteforte M, Torri V, Paris L, Bazzoni G, Lunetta C, Corbo M, Mora G, Bendotti C, Bonetto V (2011) Amyotrophic lateral sclerosis multiprotein biomarkers in peripheral blood mononuclear cells. PLoS One 6(10):e25545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Obal I, Jakab JS, Siklos L, Engelhardt JI (2001) Recruitment of activated microglia cells in the spinal cord of mice by ALS IgG. NeuroReport 12(11):2449–2452

    Article  CAS  PubMed  Google Scholar 

  • Olmos-Alonso A, Schetters ST, Sri S, Askew K, Mancuso R, Vargas-Caballero M, Holscher C, Perry VH, Gomez-Nicola D (2016) Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139(Pt 3):891–907

    Article  PubMed  PubMed Central  Google Scholar 

  • Olsen MK, Roberds SL, Ellerbrock BR, Fleck TJ, McKinley DK, Gurney ME (2001) Disease mechanisms revealed by transcription profiling in SOD1-G93A transgenic mouse spinal cord. Ann Neurol 50(6):730–740

    Article  CAS  PubMed  Google Scholar 

  • O’Rourke JG, Bogdanik L, Yanez A, Lall D, Wolf AJ, Muhammad AK, Ho R, Carmona S, Vit JP, Zarrow J, Kim KJ, Bell S, Harms MB, Miller TM, Dangler CA, Underhill DM, Goodridge HS, Lutz CM, Baloh RH (2016) C9orf72 is required for proper macrophage and microglial function in mice. Science 351(6279):1324–1329

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjaerg L, Konttinen Y, Peltonen L (2002) Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 71(3):656–662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parillaud VR, Lornet G, Monnet Y, Privat AL, Haddad AT, Brochard V, Bekaert A, de Chanville CB, Hirsch EC, Combadiere C, Hunot S, Lobsiger CS (2017) Analysis of monocyte infiltration in MPTP mice reveals that microglial CX3CR1 protects against neurotoxic over-induction of monocyte-attracting CCL2 by astrocytes. J Neuroinflammation 14(1):60

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, Hempstead BL, Littman DR, Gan WB (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155(7):1596–1609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peferoen L, Kipp M, van der Valk P, van Noort JM, Amor S (2014) Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology 141(3):302–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S, Colonna M (2015) TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Investig 125(5):2161–2170

    Article  PubMed  PubMed Central  Google Scholar 

  • Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276(5321):2045–2047

    Article  CAS  PubMed  Google Scholar 

  • Ponomarev ED, Shriver LP, Maresz K, Dittel BN (2005) Microglial cell activation and proliferation precedes the onset of CNS autoimmunity. J Neurosci Res 81(3):374–389

    Article  CAS  PubMed  Google Scholar 

  • 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(10):3369–3374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prince M, Ali GC, Guerchet M, Prina AM, Albanese E, Wu YT (2016) Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther 8(1):23

    Article  PubMed  PubMed Central  Google Scholar 

  • Pringsheim T, Jette N, Frolkis A, Steeves TD (2014) The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord 29(13):1583–1590

    Article  PubMed  Google Scholar 

  • Prinz M, Priller J, Sisodia SS, Ransohoff RM (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14(10):1227–1235

    Article  CAS  PubMed  Google Scholar 

  • Prokop S, Miller KR, Drost N, Handrick S, Mathur V, Luo J, Wegner A, Wyss-Coray T, Heppner FL (2015) Impact of peripheral myeloid cells on amyloid- pathology in Alzheimer’s disease-like mice. J Exp Med 212:1811–1818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55(5):453–462

    Article  PubMed  PubMed Central  Google Scholar 

  • Raivich G, Bohatschek M, Kloss CU, Werner A, Jones LL, Kreutzberg GW (1999) Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res Brain Res Rev 30(1):77–105

    Article  CAS  PubMed  Google Scholar 

  • Reale M, Greig NH, Kamal MA (2009) Peripheral chemo-cytokine profiles in Alzheimer’s and Parkinson’s diseases. Mini Rev Med Chem 9(10):1229–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodriguez M, Alvarez-Erviti L, Blesa FJ, Rodriguez-Oroz MC, Arina A, Melero I, Ramos LI, Obeso JA (2007) Bone-marrow-derived cell differentiation into microglia: a study in a progressive mouse model of Parkinson’s disease. Neurobiol Dis 28(3):316–325

    Article  CAS  PubMed  Google Scholar 

  • Rose S, Misharin A, Perlman H (2012) A novel Ly6C/Ly6G-based strategy to analyze the mouse splenic myeloid compartment. Cytometry A 81(4):343–350

    Article  PubMed  CAS  Google Scholar 

  • Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415):59–62

    Article  CAS  PubMed  Google Scholar 

  • Rudick RA, Ransohoff RM (1992) Cytokine secretion by multiple sclerosis monocytes. Relationship to disease activity. Arch Neurol 49(3):265–270

    Article  CAS  PubMed  Google Scholar 

  • Saederup N, Cardona AE, Croft K, Mizutani M, Cotleur AC, Tsou CL, Ransohoff RM, Charo IF (2010) Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 5(10):e13693

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sanagi T, Yuasa S, Nakamura Y, Suzuki E, Aoki M, Warita H, Itoyama Y, Uchino S, Kohsaka S, Ohsawa K (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(12):2736–2746

    CAS  PubMed  Google Scholar 

  • Sanchez-Guajardo V, Febbraro F, Kirik D, Romero-Ramos M (2010) Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson’s disease. PLoS One 5(1):e8784

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Satoh J, Kino Y, Asahina N, Takitani M, Miyoshi J, Ishida T, Saito Y (2016) TMEM119 marks a subset of microglia in the human brain. Neuropathology 36(1):39–49

    Article  CAS  PubMed  Google Scholar 

  • Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298(5594):789–791

    Article  CAS  PubMed  Google Scholar 

  • Serbina NV, Jia T, Hohl TM, Pamer EG (2008) Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol 26:421–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi C, Pamer EG (2011) Monocyte recruitment during infection and inflammation. Nat Rev Immunol 11(11):762–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA (2017) Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med 9(392):eaaf6295

    Article  PubMed  PubMed Central  Google Scholar 

  • Shibata N, Kakita A, Takahashi H, Ihara Y, Nobukuni K, Fujimura H, Sakoda S, Sasaki S, Iwata M, Morikawa S, Hirano A, Kobayashi M (2009) Activation of signal transducer and activator of transcription-3 in the spinal cord of sporadic amyotrophic lateral sclerosis patients. Neurodegener Dis 6(3):118–126

    Article  CAS  PubMed  Google Scholar 

  • Simpson EP, Henry YK, Henkel JS, Smith RG, Appel SH (2004) Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology 62(10):1758–1765

    Article  CAS  PubMed  Google Scholar 

  • Singh S, Metz I, Amor S, van der Valk P, Stadelmann C, Bruck W (2013) Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons. Acta Neuropathol 125(4):595–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solomon JN, Lewis CA, Ajami B, Corbel SY, Rossi FM, Krieger C (2006) Origin and distribution of bone marrow-derived cells in the central nervous system in a mouse model of amyotrophic lateral sclerosis. Glia 53(7):744–753

    Article  PubMed  Google Scholar 

  • Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, West BL, Green KN (2016) Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139(Pt 4):1265–1281

    Article  PubMed  PubMed Central  Google Scholar 

  • Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45(2):208–212

    Article  PubMed  Google Scholar 

  • Suarez-Calvet M, Araque Caballero MA, Kleinberger G, Bateman RJ, Fagan AM, Morris JC, Levin J, Danek A, Ewers M, Haass C, Dominantly Inherited Alzheimer Network (2016) Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury. Sci Transl Med 8(369):369ra178

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Symonds CP (1975) Multiple sclerosis and the swayback story. Lancet 1(7899):155–156

    Article  CAS  PubMed  Google Scholar 

  • Tarkowski E, Andreasen N, Tarkowski A, Blennow K (2003) Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74:1200–1205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338(5):278–285

    Article  CAS  PubMed  Google Scholar 

  • Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, Leigh PN, Banati RB (2004) Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 15(3):601–609

    Article  CAS  PubMed  Google Scholar 

  • Umeno J, Asano K, Matsushita T, Matsumoto T, Kiyohara Y, Iida M, Nakamura Y, Kamatani N, Kubo M (2011) Meta-analysis of published studies identified eight additional common susceptibility loci for Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 17(12):2407–2415

    Article  PubMed  Google Scholar 

  • van der Valk P, Amor S (2009) Preactive lesions in multiple sclerosis. Curr Opin Neurol 22(3):207–213

    PubMed  Google Scholar 

  • van Noort JM, van den Elsen PJ, van Horssen J, Geurts JJ, van der Valk P, Amor S (2011) Preactive multiple sclerosis lesions offer novel clues for neuroprotective therapeutic strategies. CNS Neurol Disord Drug Targets 10(1):68–81

    Article  PubMed  Google Scholar 

  • Varvel NH, Grathwohl SA, Degenhardt K, Resch C, Bosch A, Jucker M, Neher JJ (2015) Replacement of brain-resident myeloid cells does not alter cerebral amyloid-beta deposition in mouse models of Alzheimer’s disease. J Exp Med 212(11):1803–1809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vogel DY, Vereyken EJ, Glim JE, Heijnen PD, Moeton M, van der Valk P, Amor S, Teunissen CE, van Horssen J, Dijkstra CD (2013) Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. J Neuroinflammation 10:35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vom Berg J, Prokop S, Miller KR, Obst J, Kalin RE, Lopategui-Cabezas I, Wegner A, Mair F, Schipke CG, Peters O, Winter Y, Becher B, Heppner FL (2012) Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 18(12):1812–1819

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Sharma K, Grisotti G, Roos RP (2009) The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis. Neurobiol Dis 35(2):234–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang WY, Tan MS, Yu JT, Tan L (2015a) Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med 3(10):136

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, Gilfillan S, Krishnan GM, Sudhakar S, Zinselmeyer BH, Holtzman DM, Cirrito JR, Colonna M (2015b) TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160(6):1061–1071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, Yuan P, Mahan TE, Shi Y, Gilfillan S, Cella M, Grutzendler J, DeMattos RB, Cirrito JR, Holtzman DM, Colonna M (2016) TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med 213(5):667–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilms H, Sievers J, Dengler R, Bufler J, Deuschl G, Lucius R (2003) Intrathecal synthesis of monocyte chemoattractant protein-1 (MCP-1) in amyotrophic lateral sclerosis: further evidence for microglial activation in neurodegeneration. J Neuroimmunol 144(1–2):139–142

    Article  CAS  PubMed  Google Scholar 

  • Woollard KJ, Geissmann F (2010) Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 7(2):77–86

    Article  PubMed  PubMed Central  Google Scholar 

  • Wyss-Coray T, Mucke L (2002) Inflammation in neurodegenerative disease—a double-edged sword. Neuron 35(3):419–432

    Article  CAS  PubMed  Google Scholar 

  • Xiao Q, Zhao W, Beers DR, Yen AA, Xie W, Henkel JS, Appel SH (2007) Mutant SOD1(G93A) microglia are more neurotoxic relative to wild-type microglia. J Neurochem 102(6):2008–2019

    Article  CAS  PubMed  Google Scholar 

  • Yamasaki R, Lu H, Butovsky O, Ohno N, Rietsch AM, Cialic R, Wu PM, Doykan CE, Lin J, Cotleur AC, Kidd G, Zorlu MM, Sun N, Hu W, Liu L, Lee JC, Taylor SE, Uehlein L, Dixon D, Gu J, Floruta CM, Zhu M, Charo IF, Weiner HL, Ransohoff RM (2014) Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med 211(8):1533–1549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A, Hume DA, Perlman H, Malissen B, Zelzer E, Jung S (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38(1):79–91

    Article  CAS  PubMed  Google Scholar 

  • Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, Luo W, Colonna M, Baddeley D, Grutzendler J (2016) TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90(4):724–739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang R, Gascon R, Miller RG, Gelinas DF, Mass J, Hadlock K, Jin X, Reis J, Narvaez A, McGrath MS (2005) Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol 159(1–2):215–224

    Article  CAS  PubMed  Google Scholar 

  • Zhang R, Gascon R, Miller RG, Gelinas DF, Mass J, Lancero M, Narvaez A, McGrath MS (2006) MCP-1 chemokine receptor CCR2 is decreased on circulating monocytes in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol 179(1–2):87–93

    Article  CAS  PubMed  Google Scholar 

  • Zhang B, Gaiteri C, Bodea L-G, Wang Z, McElwee J, Podtelezhnikov Alexei A, Zhang C, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquist S, Narayanan M, Suver C, Shah H, Mahajan M, Gillis T, Mysore J, MacDonald Marcy E, Lamb John R, Bennett David A, Molony C, Stone David J, Gudnason V, Myers Amanda J, Schadt Eric E, Neumann H, Zhu J, Emilsson V (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153:707–720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao W, Beers DR, Hooten KG, Sieglaff DH, Zhang A, Kalyana-Sundaram S, Traini CM, Halsey WS, Hughes AM, Sathe GM, Livi GP, Fan GH, Appel SH (2017) Characterization of gene expression phenotype in amyotrophic lateral sclerosis monocytes. JAMA Neurol 74(6):677–685

    Article  PubMed  PubMed Central  Google Scholar 

  • Zondler L, Muller K, Khalaji S, Bliederhauser C, Ruf WP, Grozdanov V, Thiemann M, Fundel-Clemes K, Freischmidt A, Holzmann K, Strobel B, Weydt P, Witting A, Thal, Helferich AM, Hengerer B, Gottschalk KE, Hill O, Kluge M, Ludolph AC, Danzer KM, Weishaupt JH (2016) Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol 132:391–411

    Article  CAS  PubMed  Google Scholar 

  • Zrzavy T, Hametner S, Wimmer I, Butovsky O, Weiner HL, Lassmann H (2017) Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain 140:1900–1913

    Article  PubMed  PubMed Central  Google Scholar 

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Baufeld, C., O’Loughlin, E., Calcagno, N. et al. Differential contribution of microglia and monocytes in neurodegenerative diseases. J Neural Transm 125, 809–826 (2018). https://doi.org/10.1007/s00702-017-1795-7

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