Acta Neuropathologica

, Volume 126, Issue 4, pp 461–477 | Cite as

Microglia actions in Alzheimer’s disease

  • Stefan Prokop
  • Kelly R. Miller
  • Frank L. HeppnerEmail author


The identification of microglia-associated, neurological disease-causing mutations in patients, combined with studies in mouse models has highlighted microglia, the brain’s intrinsic myeloid cells, as key modulators of pathogenesis and disease progression in neurodegenerative diseases. In Alzheimer’s disease (AD) in particular, the activation and accumulation of microglial cells around β-Amyloid (Aβ) plaques has long been described and is believed to result in chronic neuroinflammation—a term that, despite being commonly used, lacks a precise definition. This seemingly directed response of microglia to amyloid deposits conflicts with the fact that the increasing buildup of Aβ plaques is not inhibited by these cells during disease progression. While recent evidence suggests that microglia lose their intrinsic beneficial function during the course of AD and may even acquire a “toxic” phenotype over time, Aβ may also simply not be an appropriate trigger to induce phagocytosis and degradation by microglia in vivo. As recent experimental evidence has indicated the importance of the microglia in AD pathogenesis, future efforts aimed at tackling this disease via utilization or modulation of microglia or factors therefrom appear to be an exciting and challenging research front.


Microglia Alzheimer’s disease Phagocytosis Activation Cellular senescence 




Soluble Amyloid-β


Alzheimer’s disease


Bone marrow mononuclear cells


C-C chemokine receptor type 2


Cluster of differentiation


Central nervous system


Colony stimulating factor 1 receptor


CX3C chemokine receptor 1


Chemokine (C-X3-C motif) ligand 1 (Fraktalkine)


Genome wide association study


Hereditary diffuse leukoencephalopathy with spheroids


Human leucocyte antigen


Herpes-simplex virus thymidine kinase




Late-onset Alzheimer’s disease




Monocyte chemoattractant protein 1


Macrophage colony-stimulating factor


Major histocompatibility complex


Macrophage inflammatory protein


Monophosphoryl lipid A


NACHT, LRR and PYD domains-containing protein 3


Nonsteroidal anti-inflammatory drugs


Receptor for advanced glycation end products


Triggering receptor expressed on myeloid cells 2


Tumor necrosis factor


Transforming growth factor



This work was supported by the Deutsche Forschungsgemeinschaft (SFB TRR 43 to F.L.H. and S.P., and NeuroCure Exc 257 to F.L.H.), the US National Institutes of Health (NINDS R01 NS046006 to F.L.H.), and the Federal Ministry of Education and Research (BMBF; Kompetenznetz Degenerative Demenzen to S.P. and F.L.H.). We thank Wolfgang J. Streit, University of Florida, Gainesville, for image Fig. 3.

Conflict of interest

F.L.H holds a patent application by the Charité–Universitätsmedizin Berlin entitled “Modulators of IL-12 and/or IL-23 for the Prevention or Treatment of Alzheimer’s Disease” (PCT/EP2012/050066).


  1. 1.
    Adolfsson O, Pihlgren M, Toni N et al (2012) An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci 32:9677–9689. doi: 10.1523/JEUROSCI.4742-11.2012 PubMedGoogle Scholar
  2. 2.
    Aisen PS, Schafer KA, Grundman M et al (2003) Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289:2819–2826. doi: 10.1001/jama.289.21.2819 PubMedGoogle Scholar
  3. 3.
    Akerblom M, Sachdeva R, Quintino L et al (2013) Visualization and genetic modification of resident brain microglia using lentiviral vectors regulated by microRNA-9. Nat Commun 4:1770. doi: 10.1038/ncomms2801 PubMedGoogle Scholar
  4. 4.
    Akiyama H, Barger S, Barnum S et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421PubMedGoogle Scholar
  5. 5.
    Akiyama H, Itagaki S, McGeer PL (1988) Major histocompatibility complex antigen expression on rat microglia following epidural kainic acid lesions. J Neurosci Res 20:147–157. doi: 10.1002/jnr.490200202 PubMedGoogle Scholar
  6. 6.
    Ard MD, Cole GM, Wei J, Mehrle AP, Fratkin JD (1996) Scavenging of Alzheimer’s amyloid beta-protein by microglia in culture. J Neurosci Res 43:190–202. doi: 10.1002/(SICI)1097-4547(19960115)43:2<190:AID-JNR7>3.0.CO;2-B PubMedGoogle Scholar
  7. 7.
    Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE (2003) A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci 23:2665–2674PubMedGoogle Scholar
  8. 8.
    Bard F, Cannon C, Barbour R et al (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6:916–919. doi: 10.1038/78682 PubMedGoogle Scholar
  9. 9.
    Bertram L, Lange C, Mullin K et al (2008) Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am J Hum Genet 83:623–632. doi: 10.1016/j.ajhg.2008.10.008 PubMedGoogle Scholar
  10. 10.
    Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT (2010) Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68:19–31. doi: 10.1016/j.neuron.2010.08.023 PubMedGoogle Scholar
  11. 11.
    Boche D, Perry VH, Nicoll JA (2013) Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39:3–18. doi: 10.1111/nan.12011 PubMedGoogle Scholar
  12. 12.
    Boissonneault V, Filali M, Lessard M, Relton J, Wong G, Rivest S (2009) Powerful beneficial effects of macrophage colony-stimulating factor on beta-amyloid deposition and cognitive impairment in Alzheimer’s disease. Brain 132:1078–1092. doi: 10.1093/brain/awn331 PubMedGoogle Scholar
  13. 13.
    Boyd TD, Bennett SP, Mori T et al (2010) GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. J Alzheimer’s Dis 21:507–518. doi: 10.3233/JAD-2010-091471 Google Scholar
  14. 14.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedGoogle Scholar
  15. 15.
    Bradshaw EM, Chibnik LB, Keenan BT et al (2013) CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci doi: 10.1038/nn.3435
  16. 16.
    Breitner JC, Baker LD, Montine TJ et al (2011) Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimer’s Dementia 7:402–411. doi: 10.1016/j.jalz.2010.12.014 PubMedGoogle Scholar
  17. 17.
    Buttini M, Limonta S, Boddeke HW (1996) Peripheral administration of lipopolysaccharide induces activation of microglial cells in rat brain. Neurochem Int 29:25–35PubMedGoogle Scholar
  18. 18.
    Cameron B, Tse W, Lamb R, Li X, Lamb BT, Landreth GE (2012) Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer’s disease. J Neurosci 32:15112–15123. doi: 10.1523/JNEUROSCI.1729-12.2012 PubMedGoogle Scholar
  19. 19.
    Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740. doi: 10.1038/nrm2233 PubMedGoogle Scholar
  20. 20.
    Chen SK, Tvrdik P, Peden E et al (2010) Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141:775–785. doi: 10.1016/j.cell.2010.03.055 PubMedGoogle Scholar
  21. 21.
    Choi SH, Aid S, Caracciolo L et al (2013) Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer’s disease. J Neurochem 124:59–68. doi: 10.1111/jnc.12059 PubMedGoogle Scholar
  22. 22.
    Cimino PJ, Yang Y, Li X et al (2013) Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of Alzheimer’s disease. Exp Mol Pathol 94:366–371. doi: 10.1016/j.yexmp.2013.01.002 PubMedGoogle Scholar
  23. 23.
    Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP (2006) Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflamm 3:27. doi: 10.1186/1742-2094-3-27 Google Scholar
  24. 24.
    Combs CK, Johnson DE, Cannady SB, Lehman TM, Landreth GE (1999) Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins. J Neurosci 19:928–939PubMedGoogle Scholar
  25. 25.
    Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE (2000) Inflammatory mechanisms in Alzheimer’s disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci 20:558–567PubMedGoogle Scholar
  26. 26.
    Conde JR, Streit WJ (2006) Effect of aging on the microglial response to peripheral nerve injury. Neurobiol Aging 27:1451–1461. doi: 10.1016/j.neurobiolaging.2005.07.012 PubMedGoogle Scholar
  27. 27.
    Coraci IS, Husemann J, Berman JW et al (2002) CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer’s disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol 160:101–112PubMedGoogle Scholar
  28. 28.
    Craggs RI, Webster HD (1985) Ia antigens in the normal rat nervous system and in lesions of experimental allergic encephalomyelitis. Acta Neuropathol 68:263–272PubMedGoogle Scholar
  29. 29.
    Damani MR, Zhao L, Fontainhas AM, Amaral J, Fariss RN, Wong WT (2011) Age-related alterations in the dynamic behavior of microglia. Aging Cell 10:263–276. doi: 10.1111/j.1474-9726.2010.00660.x PubMedGoogle Scholar
  30. 30.
    DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM (2002) Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295:2264–2267. doi: 10.1126/science.1067568 PubMedGoogle Scholar
  31. 31.
    Derecki NC, Cronk JC, Lu Z et al (2012) Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484:105–109. doi: 10.1038/nature10907 PubMedGoogle Scholar
  32. 32.
    DiCarlo G, Wilcock D, Henderson D, Gordon M, Morgan D (2001) Intrahippocampal LPS injections reduce Abeta load in APP + PS1 transgenic mice. Neurobiol Aging 22:1007–1012PubMedGoogle Scholar
  33. 33.
    Doi Y, Mizuno T, Maki Y et al (2009) Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid {beta} neurotoxicity in in vitro and in vivo models of Alzheimer’s disease. Am J Pathol 175: 2121–2132. doi: 10.2353/ajpath.2009.090418 Google Scholar
  34. 34.
    Du Yan S, Zhu H, Fu J et al (1997) Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease. Proc Natl Acad Sci USA 94:5296–5301PubMedGoogle Scholar
  35. 35.
    Eikelenboom P, Bate C, Van Gool WA et al (2002) Neuroinflammation in Alzheimer’s disease and prion disease. Glia 40: 232–239. doi: 10.1002/glia.10146 Google Scholar
  36. 36.
    El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD (1996) Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382:716–719. doi: 10.1038/382716a0 PubMedGoogle Scholar
  37. 37.
    El Khoury J, Toft M, Hickman SE et al (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13:432–438. doi: 10.1038/nm1555 PubMedGoogle Scholar
  38. 38.
    Fonseca MI, Ager RR, Chu SH (2009) Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer’s disease. J Immunol 183:1375–1383. doi: 10.4049/jimmunol.0901005 PubMedGoogle Scholar
  39. 39.
    Fonseca MI, Zhou J, Botto M, Tenner AJ (2004) Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer’s disease. J Neurosci 24:6457–6465. doi: 10.1523/JNEUROSCI.0901-04.2004 PubMedGoogle Scholar
  40. 40.
    Frackowiak J, Wisniewski HM, Wegiel J, Merz GS, Iqbal K, Wang KC (1992) Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol 84:225–233PubMedGoogle Scholar
  41. 41.
    Frank S, Burbach GJ, Bonin M et al (2008) TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia 56:1438–1447. doi: 10.1002/glia.20710 PubMedGoogle Scholar
  42. 42.
    Frautschy SA, Cole GM, Baird A (1992) Phagocytosis and deposition of vascular beta-amyloid in rat brains injected with Alzheimer beta-amyloid. Am J Pathol 140:1389–1399PubMedGoogle Scholar
  43. 43.
    Frautschy SA, Yang F, Irrizarry M et al (1998) Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 152:307–317PubMedGoogle Scholar
  44. 44.
    Frenkel D, Wilkinson K, Zhao L et al Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat Commun 4:2030. doi: 10.1038/ncomms3030
  45. 45.
    Fuhrmann M, Bittner T, Jung CK et al (2010) Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 13:411–413. doi: 10.1038/nn.2511 PubMedGoogle Scholar
  46. 46.
    Gandy S, Heppner FL (2013) Microglia as dynamic and essential components of the amyloid hypothesis. Neuron 78:575–577. doi: 10.1016/j.neuron.2013.05.007 PubMedGoogle Scholar
  47. 47.
    Garcia-Alloza M, Ferrara BJ, Dodwell SA, Hickey GA, Hyman BT, Bacskai BJ (2007) A limited role for microglia in antibody mediated plaque clearance in APP mice. Neurobiol Dis 28:286–292. doi: 10.1016/j.nbd.2007.07.019 PubMedGoogle Scholar
  48. 48.
    Ginhoux F, Greter M, Leboeuf M et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845. doi: 10.1126/science.1194637 PubMedGoogle Scholar
  49. 49.
    Golde TE, Das P, Levites Y (2009) Quantitative and mechanistic studies of Abeta immunotherapy. CNS Neurol Disord 8:31–49Google Scholar
  50. 50.
    Grathwohl SA, Kalin RE, Bolmont T et al (2009) Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neurosci 12:1361–1363. doi: 10.1038/nn.2432 PubMedGoogle Scholar
  51. 51.
    Griciuc A, Serrano-Pozo A, Parrado AR et al Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78:631–643. doi: 10.1016/j.neuron.2013.04.014
  52. 52.
    Griffin WS, Stanley LC, Ling C et al (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 86:7611–7615PubMedGoogle Scholar
  53. 53.
    Guerreiro R, Wojtas A, Bras J et al (2012) TREM2 variants in Alzheimer’s disease. N Engl J Med. doi: 10.1056/NEJMoa1211851
  54. 54.
    Ha TY, Chang KA, Kim J et al (2010) S100a9 knockdown decreases the memory impairment and the neuropathology in Tg2576 mice, AD animal model. PloS one 5:e8840. doi: 10.1371/journal.pone.0008840 PubMedGoogle Scholar
  55. 55.
    Halle A, Hornung V, Petzold GC et al (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9:857–865. doi: 10.1038/ni.1636 PubMedGoogle Scholar
  56. 56.
    Hayes GM, Woodroofe MN, Cuzner ML (1987) Microglia are the major cell type expressing MHC class II in human white matter. J Neurol Sci 80:25–37PubMedGoogle Scholar
  57. 57.
    Heneka MT, Kummer MP, Stutz A et al (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678. doi: 10.1038/nature11729 PubMedGoogle Scholar
  58. 58.
    Heneka MT, Kummer MP, Weggen S (2011) Molecular mechanisms and therapeutic application of NSAIDs and derived compounds in Alzheimer’s disease. Curr Alzheimer Res 8:115–131PubMedGoogle Scholar
  59. 59.
    Heneka MT, Nadrigny F, Regen T et al (2010) Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA 107:6058–6063. doi: 10.1073/pnas.0909586107 PubMedGoogle Scholar
  60. 60.
    Heppner FL, Greter M, Marino D et al (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11:146–152. doi: 10.1038/nm1177 PubMedGoogle Scholar
  61. 61.
    Herber DL, Mercer M, Roth LM et al (2007) Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice. J Neuroimmune Pharmacol 2:222–231. doi: 10.1007/s11481-007-9069-z PubMedGoogle Scholar
  62. 62.
    Herber DL, Roth LM, Wilson D et al (2004) Time-dependent reduction in Abeta levels after intracranial LPS administration in APP transgenic mice. Exp Neurol 190:245–253. doi: 10.1016/j.expneurol.2004.07.007 PubMedGoogle Scholar
  63. 63.
    Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28:8354–8360. doi: 10.1523/JNEUROSCI.0616-08.2008 PubMedGoogle Scholar
  64. 64.
    Hollingworth P, Harold D, Sims R (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43:429–435. doi: 10.1038/ng.803 PubMedGoogle Scholar
  65. 65.
    Hsieh CL, Koike M, Spusta SC et al (2009) A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem 109:1144–1156. doi: 10.1111/j.1471-4159.2009.06042.x PubMedGoogle Scholar
  66. 66.
    Hu WT, Holtzman DM, Fagan AM et al (2012) Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease. Neurology 79:897–905. doi: 10.1212/WNL.0b013e318266fa70 PubMedGoogle Scholar
  67. 67.
    Hyman BT, Marzloff K, Arriagada PV (1993) The lack of accumulation of senile plaques or amyloid burden in Alzheimer’s disease suggests a dynamic balance between amyloid deposition and resolution. J Neuropathol Exp Neurol 52:594–600PubMedGoogle Scholar
  68. 68.
    Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D (1989) Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol 24:173–182PubMedGoogle Scholar
  69. 69.
    Jimenez S, Baglietto-Vargas D, Caballero C et al (2008) Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 28:11650–11661. doi: 10.1523/JNEUROSCI.3024-08.2008 PubMedGoogle Scholar
  70. 70.
    Jonsson T, Stefansson H, Ph DS et al (2012) Variant of TREM2 Associated with the Risk of Alzheimer’s Disease. N Engl J Med. doi: 10.1056/NEJMoa1211103
  71. 71.
    Keene CD, Chang RC, Lopez-Yglesias AH et al (2010) Suppressed accumulation of cerebral amyloid beta peptides in aged transgenic Alzheimer’s disease mice by transplantation with wild-type or prostaglandin E2 receptor subtype 2-null bone marrow. Am J Pathol 177:346–354. doi: 10.2353/ajpath.2010.090840 PubMedGoogle Scholar
  72. 72.
    Kierdorf K, Erny D, Goldmann T et al (2013) Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci. doi: 10.1038/nn.3318
  73. 73.
    Kim WS, Li H, Ruberu K et al (2013) Deletion of Abca7 increases cerebral amyloid-beta accumulation in the J20 mouse model of Alzheimer’s disease. J Neurosci 33:4387–4394. doi: 10.1523/JNEUROSCI.4165-12.2013 PubMedGoogle Scholar
  74. 74.
    Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM (2005) Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci 25:8843–8853. doi: 10.1523/JNEUROSCI.2868-05.2005 PubMedGoogle Scholar
  75. 75.
    Klegeris A, McGeer PL (1997) beta-amyloid protein enhances macrophage production of oxygen free radicals and glutamate. J Neurosci Res 49:229–235PubMedGoogle Scholar
  76. 76.
    Koenigsknecht-Talboo J, Meyer-Luehmann M, Parsadanian M et al (2008) Rapid microglial response around amyloid pathology after systemic anti-Abeta antibody administration in PDAPP mice. J Neurosci 28:14156–14164. doi: 10.1523/JNEUROSCI.4147-08.2008 PubMedGoogle Scholar
  77. 77.
    Krabbe G, Halle A, Matyash V et al Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PloS one 8:e60921. doi: 10.1371/journal.pone.0060921
  78. 78.
    Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318PubMedGoogle Scholar
  79. 79.
    Kummer MP, Vogl T, Axt D et al (2012) Mrp14 deficiency ameliorates amyloid beta burden by increasing microglial phagocytosis and modulation of amyloid precursor protein processing. J Neurosci 32:17824–17829. doi: 10.1523/JNEUROSCI.1504-12.2012 PubMedGoogle Scholar
  80. 80.
    Lee DC, Rizer J, Selenica ML et al (2010) LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice. J Neuroinflamm 7:56. doi: 10.1186/1742-2094-7-56 Google Scholar
  81. 81.
    Lee S, Varvel NH, Konerth ME et al (2010) CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol 177:2549–2562. doi: 10.2353/ajpath.2010.100265 PubMedGoogle Scholar
  82. 82.
    Lim GP, Yang F, Chu T et al (2000) Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 20:5709–5714PubMedGoogle Scholar
  83. 83.
    Lim JE, Kou J, Song M et al (2011) MyD88 deficiency ameliorates beta-amyloidosis in an animal model of Alzheimer’s disease. Am J Pathol 179:1095–1103. doi: 10.1016/j.ajpath.2011.05.045 PubMedGoogle Scholar
  84. 84.
    Lopes KO, Sparks DL, Streit WJ (2008) Microglial dystrophy in the aged and Alzheimer’s disease brain is associated with ferritin immunoreactivity. Glia 56:1048–1060. doi: 10.1002/glia.20678 PubMedGoogle Scholar
  85. 85.
    Lue LF, Rydel R, Brigham EF et al (2001) Inflammatory repertoire of Alzheimer’s disease and nondemented elderly microglia in vitro. Glia 35:72–79PubMedGoogle Scholar
  86. 86.
    Lue LF, Walker DG (2002) Modeling Alzheimer’s disease immune therapy mechanisms: interactions of human postmortem microglia with antibody-opsonized amyloid beta peptide. J Neurosci Res 70:599–610. doi: 10.1002/jnr.10422 PubMedGoogle Scholar
  87. 87.
    Lyketsos CG, Breitner JC, Green RC et al (2007) Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology 68:1800–1808. doi: 10.1212/01.wnl.0000260269.93245.d2 PubMedGoogle Scholar
  88. 88.
    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 28:6333–6341. doi: 10.1523/JNEUROSCI.0829-08.2008 PubMedGoogle Scholar
  89. 89.
    Manczak M, Mao P, Nakamura K, Bebbington C, Park B, Reddy PH (2009) Neutralization of granulocyte macrophage colony-stimulating factor decreases amyloid beta 1-42 and suppresses microglial activity in a transgenic mouse model of Alzheimer’s disease. Hum Mol Genet 18:3876–3893. doi: 10.1093/hmg/ddp331 PubMedGoogle Scholar
  90. 90.
    Mandrekar S, Jiang Q, Lee CY, Koenigsknecht-Talboo J, Holtzman DM, Landreth GE (2009) Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J Neurosci 29:4252–4262. doi: 10.1523/JNEUROSCI.5572-08.2009 PubMedGoogle Scholar
  91. 91.
    Martin-Moreno AM, Brera B, Spuch C et al (2012) Prolonged oral cannabinoid administration prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflamm 9:8. doi: 10.1186/1742-2094-9-8 Google Scholar
  92. 92.
    McDonald DR, Brunden KR, Landreth GE (1997) Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. J Neurosci 17:2284–2294PubMedGoogle Scholar
  93. 93.
    McGeer PL, Akiyama H, Itagaki S, McGeer EG (1989) Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci Lett 107:341–346PubMedGoogle Scholar
  94. 94.
    McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79:195–200PubMedGoogle Scholar
  95. 95.
    McGeer PL, Schulzer M, McGeer EG (1996) Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology 47:425–432PubMedGoogle Scholar
  96. 96.
    Meda L, Baron P, Prat E et al (1999) Proinflammatory profile of cytokine production by human monocytes and murine microglia stimulated with beta-amyloid[25–35]. J Neuroimmunol 93:45–52PubMedGoogle Scholar
  97. 97.
    Melchior B, Garcia AE, Hsiung BK et al (2010) Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer’s disease. ASN Neuro 2:e00037. doi: 10.1042/AN20100010 PubMedGoogle Scholar
  98. 98.
    Michaud JP, Halle M, Lampron A et al (2013) Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology. Proc Natl Acad Sci USA 110:1941–1946. doi: 10.1073/pnas.1215165110 PubMedGoogle Scholar
  99. 99.
    Mildner A, Schlevogt B, Kierdorf K et al (2011) Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J Neurosci 31:11159–11171. doi: 10.1523/JNEUROSCI.6209-10.2011 PubMedGoogle Scholar
  100. 100.
    Miller KR, Streit WJ (2007) The effects of aging, injury and disease on microglial function: a case for cellular senescence. Neuron Glia Biol 3:245–253. doi: 10.1017/S1740925X08000136 PubMedGoogle Scholar
  101. 101.
    Mirra SS, Heyman A, McKeel D et al (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486PubMedGoogle Scholar
  102. 102.
    Mizuno T, Doi Y, Mizoguchi H et al (2011) Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-beta neurotoxicity. Am J Pathol 179:2016–2027. doi: 10.1016/j.ajpath.2011.06.011 Google Scholar
  103. 103.
    Naert G, Rivest S (2011) CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer’s disease. J Neurosci 31:6208–6220. doi: 10.1523/JNEUROSCI.0299-11.2011 PubMedGoogle Scholar
  104. 104.
    Naj AC, Jun G, Beecham GW et al Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 43:436-441. doi: 10.1038/ng.801
  105. 105.
    Nash KR, Lee DC, Hunt Jr JB et al (2013) Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy. Neurobiol Aging. doi: 10.1016/j.neurobiolaging.2012.12.011
  106. 106.
    Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9:448–452. doi: 10.1038/nm840 PubMedGoogle Scholar
  107. 107.
    Njie EG, Boelen E, Stassen FR, Steinbusch HW, Borchelt DR, Streit WJ (2012) Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging 33:195 e191–195 e112. doi: 10.1016/j.neurobiolaging.2010.05.008 Google Scholar
  108. 108.
    Paolicelli RC, Bolasco G, Pagani F et al (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458. doi: 10.1126/science.1202529 PubMedGoogle Scholar
  109. 109.
    Paresce DM, Ghosh RN, Maxfield FR (1996) Microglial cells internalize aggregates of the Alzheimer’s disease amyloid beta-protein via a scavenger receptor. Neuron 17:553–565PubMedGoogle Scholar
  110. 110.
    Qin L, Wu X, Block ML et al (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462. doi: 10.1002/glia.20467 PubMedGoogle Scholar
  111. 111.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344. doi: 10.1056/NEJMra0909142 PubMedGoogle Scholar
  112. 112.
    Quinn J, Montine T, Morrow J, Woodward WR, Kulhanek D, Eckenstein F (2003) Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer’s disease. J Neuroimmunol 137:32–41PubMedGoogle Scholar
  113. 113.
    Rademakers R, Baker M, Nicholson AM et al (2012) Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 44:200–205. doi: 10.1038/ng.1027 Google Scholar
  114. 114.
    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 30:77–105PubMedGoogle Scholar
  115. 115.
    Reed-Geaghan EG, Reed QW, Cramer PE, Landreth GE (2010) Deletion of CD14 attenuates Alzheimer’s disease pathology by influencing the brain’s inflammatory milieu. J Neurosci 30:15369–15373. doi: 10.1523/JNEUROSCI.2637-10.2010 PubMedGoogle Scholar
  116. 116.
    Richard KL, Filali M, Prefontaine P, Rivest S (2008) Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer’s disease. J Neurosci 28:5784–5793. doi: 10.1523/JNEUROSCI.1146-08.2008 PubMedGoogle Scholar
  117. 117.
    Rogers J, Luber-Narod J, Styren SD, Civin WH (1988) Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 9:339–349PubMedGoogle Scholar
  118. 118.
    Rogers J, Strohmeyer R, Kovelowski CJ, Li R (2002) Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia 40:260–269. doi: 10.1002/glia.10153 PubMedGoogle Scholar
  119. 119.
    Salloway S, Sperling R, Gilman S et al (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73:2061–2070. doi: 10.1212/WNL.0b013e3181c67808 PubMedGoogle Scholar
  120. 120.
    Sanchez-Ramos J, Song S, Sava V et al (2009) Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer’s mice. Neuroscience 163:55–72. doi: 10.1016/j.neuroscience.2009.05.071 PubMedGoogle Scholar
  121. 121.
    Schenk D, Barbour R, Dunn W et al (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177. doi: 10.1038/22124 PubMedGoogle Scholar
  122. 122.
    Schulz C, Gomez Perdiguero E, Chorro L et al (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:86–90. doi: 10.1126/science.1219179 PubMedGoogle Scholar
  123. 123.
    Seabrook TJ, Jiang L, Maier M, Lemere CA (2006) Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice. Glia 53:776–782. doi: 10.1002/glia.20338 PubMedGoogle Scholar
  124. 124.
    Shen Y, Li R, McGeer EG, McGeer PL (1997) Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain. Brain Res 769:391–395PubMedGoogle Scholar
  125. 125.
    Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE (2003) Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis 14:133–145PubMedGoogle Scholar
  126. 126.
    Shigematsu K, McGeer PL, Walker DG, Ishii T, McGeer EG (1992) Reactive microglia/macrophages phagocytose amyloid precursor protein produced by neurons following neural damage. J Neurosci Res 31:443–453. doi: 10.1002/jnr.490310306 PubMedGoogle Scholar
  127. 127.
    Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Investig 122:787–795. doi: 10.1172/JCI59643 PubMedGoogle Scholar
  128. 128.
    Sierra A, Encinas JM, Deudero JJ et al (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7:483–495. doi: 10.1016/j.stem.2010.08.014 PubMedGoogle Scholar
  129. 129.
    Simard AR, Soulet D, Gowing G, Julien JP, Rivest S (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49:489–502. doi: 10.1016/j.neuron.2006.01.022 PubMedGoogle Scholar
  130. 130.
    Smetanka AM, Yee KT, Lund RD (1990) Differential induction of class I and II MHC antigen expression by degenerating myelinated and unmyelinated axons. Brain Res 521:343–346PubMedGoogle Scholar
  131. 131.
    Soininen H, West C, Robbins J, Niculescu L (2007) Long-term efficacy and safety of celecoxib in Alzheimer’s disease. Dement Geriatr Cogn Disord 23:8–21. doi: 10.1159/000096588 PubMedGoogle Scholar
  132. 132.
    Song M, Jin J, Lim JE et al (2011) TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflamm 8:92. doi: 10.1186/1742-2094-8-92 Google Scholar
  133. 133.
    Song M, Xiong JX, Wang YY, Tang J, Zhang B, Bai Y (2012) VIP enhances phagocytosis of fibrillar beta-amyloid by microglia and attenuates amyloid deposition in the brain of APP/PS1 mice. PLoS ONE 7:e29790. doi: 10.1371/journal.pone.0029790 PubMedGoogle Scholar
  134. 134.
    Stalder M, Deller T, Staufenbiel M, Jucker M (2001) 3D-Reconstruction of microglia and amyloid in APP23 transgenic mice: no evidence of intracellular amyloid. Neurobiol Aging 22:427–434PubMedGoogle Scholar
  135. 135.
    Stalder M, Phinney A, Probst A, Sommer B, Staufenbiel M, Jucker M (1999) Association of microglia with amyloid plaques in brains of APP23 transgenic mice. Am J Pathol 154:1673–1684. doi: 10.1016/S0002-9440(10)65423-5 PubMedGoogle Scholar
  136. 136.
    Streit WJ (2004) Microglia and Alzheimer’s disease pathogenesis. J Neurosci Res 77:1–8. doi: 10.1002/jnr.20093 PubMedGoogle Scholar
  137. 137.
    Streit WJ, Braak H, Xue QS, Bechmann I (2009) Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 118:475–485. doi: 10.1007/s00401-009-0556-6 PubMedGoogle Scholar
  138. 138.
    Streit WJ, Graeber MB, Kreutzberg GW (1989) Expression of Ia antigen on perivascular and microglial cells after sublethal and lethal motor neuron injury. Exp Neurol 105:115–126PubMedGoogle Scholar
  139. 139.
    Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45:208–212. doi: 10.1002/glia.10319 PubMedGoogle Scholar
  140. 140.
    Streit WJ, Walter SA, Pennell NA (1999) Reactive microgliosis. Prog Neurobiol 57:563–581PubMedGoogle Scholar
  141. 141.
    Strohmeyer R, Shen Y, Rogers J (2000) Detection of complement alternative pathway mRNA and proteins in the Alzheimer’s disease brain. Brain Res Mol Brain Res 81:7–18PubMedGoogle Scholar
  142. 142.
    Styren SD, Civin WH, Rogers J (1990) Molecular, cellular, and pathologic characterization of HLA-DR immunoreactivity in normal elderly and Alzheimer’s disease brain. Exp Neurol 110:93–104PubMedGoogle Scholar
  143. 143.
    Sudduth TL, Schmitt FA, Nelson PT, Wilcock DM (2013) Neuroinflammatory phenotype in early Alzheimer’s disease. Neurobiol Aging 34:1051–1059. doi: 10.1016/j.neurobiolaging.2012.09.012 PubMedGoogle Scholar
  144. 144.
    Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H (2007) TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 4:e124. doi: 10.1371/journal.pmed.0040124 PubMedGoogle Scholar
  145. 145.
    Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201:647–657. doi: 10.1084/jem.20041611 PubMedGoogle Scholar
  146. 146.
    Tatrai E, Brozik M, Kovacikova Z, Horvath M (2005) The effect of asbestos and stone-wool fibres on some chemokines and redox system of pulmonary alveolar macrophages and pneumocytes type II. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 149:357–361PubMedGoogle Scholar
  147. 147.
    Terry RD, Gonatas NK, Weiss M (1964) Ultrastructural studies in Alzheimer’s presenile dementia. Am J Pathol 44:269–297PubMedGoogle Scholar
  148. 148.
    Thal LJ, Ferris SH, Kirby L et al (2005) A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 30:1204–1215. doi: 10.1038/sj.npp.1300690 PubMedGoogle Scholar
  149. 149.
    Town T, Laouar Y, Pittenger C et al (2008) Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 14:681–687. doi: 10.1038/nm1781 PubMedGoogle Scholar
  150. 150.
    van der Wal EA, Gomez-Pinilla F, Cotman CW (1993) Transforming growth factor-beta 1 is in plaques in Alzheimer and Down pathologies. NeuroReport 4:69–72PubMedGoogle Scholar
  151. 151.
    Varnum MM, Ikezu T (2012) The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Archivum immunologiae et therapiae experimentalis 60:251–266. doi: 10.1007/s00005-012-0181-2 PubMedGoogle Scholar
  152. 152.
    Varvel NH, Grathwohl SA, Baumann F et al (2012) Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc Natl Acad Sci USA 109:18150–18155. doi: 10.1073/pnas.1210150109 PubMedGoogle Scholar
  153. 153.
    Vom Berg J, Prokop S, Miller KR et al (2012) Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 18:1812–1819. doi: 10.1038/nm.2965 PubMedGoogle Scholar
  154. 154.
    Walker DG, Kim SU, McGeer PL (1995) Complement and cytokine gene expression in cultured microglial derived from postmortem human brains. J Neurosci Res 40:478–493. doi: 10.1002/jnr.490400407 PubMedGoogle Scholar
  155. 155.
    Walker DG, Lue LF, Beach TG (2001) Gene expression profiling of amyloid beta peptide-stimulated human post-mortem brain microglia. Neurobiol Aging 22:957–966PubMedGoogle Scholar
  156. 156.
    Wang A, Das P, Switzer RC III, Golde TE, Jankowsky JL (2011) Robust amyloid clearance in a mouse model of Alzheimer’s disease provides novel insights into the mechanism of amyloid-beta immunotherapy. J Neurosci 31:4124–4136. doi: 10.1523/JNEUROSCI.5077-10.2011 PubMedGoogle Scholar
  157. 157.
    Weldon DT, Rogers SD, Ghilardi JR et al (1998) Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci 18:2161–2173PubMedGoogle Scholar
  158. 158.
    Wilcock DM, DiCarlo G, Henderson D et al (2003) Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci 23:3745–3751PubMedGoogle Scholar
  159. 159.
    Wilcock DM, Munireddy SK, Rosenthal A, Ugen KE, Gordon MN, Morgan D (2004) Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiol Dis 15:11–20PubMedGoogle Scholar
  160. 160.
    Wilcock DM, Rojiani A, Rosenthal A et al (2004) Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J Neurosci 24:6144–6151. doi: 10.1523/JNEUROSCI.1090-04.2004 PubMedGoogle Scholar
  161. 161.
    Wisniewski HM, Barcikowska M, Kida E (1991) Phagocytosis of beta/A4 amyloid fibrils of the neuritic neocortical plaques. Acta Neuropathol 81:588–590PubMedGoogle Scholar
  162. 162.
    Wisniewski HM, Wegiel J, Wang KC, Kujawa M, Lach B (1989) Ultrastructural studies of the cells forming amyloid fibers in classical plaques. Can J Neurol Sci 16:535–542PubMedGoogle Scholar
  163. 163.
    Wyss-Coray T, Lin C, Sanan DA, Mucke L, Masliah E (2000) Chronic overproduction of transforming growth factor-beta1 by astrocytes promotes Alzheimer’s disease-like microvascular degeneration in transgenic mice. Am J Pathol 156:139–150PubMedGoogle Scholar
  164. 164.
    Wyss-Coray T, Lin C, Yan F et al (2001) TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 7:612–618. doi: 10.1038/87945 PubMedGoogle Scholar
  165. 165.
    Wyss-Coray T, Masliah E, Mallory M et al (1997) Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer’s disease. Nature 389:603–606. doi: 10.1038/39321 PubMedGoogle Scholar
  166. 166.
    Wyss-Coray T, Yan F, Lin AH et al (2002) Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc Natl Acad Sci USA 99:10837–10842. doi: 10.1073/pnas.162350199 PubMedGoogle Scholar
  167. 167.
    Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT (2011) PPARgamma/RXRalpha-induced and CD36-mediated microglial amyloid-beta phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci 32:17321–17331. doi: 10.1523/JNEUROSCI.1569-12.2012 Google Scholar
  168. 168.
    Yan Q, Zhang J, Liu H et al (2003) Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer’s disease. J Neurosci 23:7504–7509PubMedGoogle Scholar
  169. 169.
    Zhang B, Gaiteri C, Bodea LG et al (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153:707–720. doi: 10.1016/j.cell.2013.03.030 PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Stefan Prokop
    • 1
  • Kelly R. Miller
    • 1
  • Frank L. Heppner
    • 1
    Email author
  1. 1.Department of NeuropathologyCharité, Universitätsmedizin BerlinBerlinGermany

Personalised recommendations