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Microglia in the Alzheimers brain: a help or a hindrance?

Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204, USA

Alzheimer’s disease (AD), the leading cause of dementia, is a complex neurodegenerative disorder. The AD brain is characterized by the presence of Amyloid-β (Aβ) plaques, neurofibrillary tangles, and an increased inflammatory response. Microglia, the chief immune cells of the central nervous system, have been implicated in AD due to their strong association with Aβ plaques. The role of inflammation associated with microglia has been hotly contested in development of Alzheimer’s disease. A growing amount of genetic studies have implicated microglia in late-onset AD and their role in Aβ clearance. Although traditionally microglia have been considered to be either in resting or activated states, these cells are now known to exist in multiple heterogeneous populations and altered roles that appear to impact pathological states of the Alzheimer’s brain.
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Keywords Alzheimer’s disease; late-onset AD; inflammation; microglia; amyloid beta

Citation: Craig T. Vollert, Jason L. Eriksen. Microglia in the Alzheimers brain: a help or a hindrance?. AIMS Neuroscience, 2014, 1(3): 210-224. doi: 10.3934/Neuroscience.2014.3.210


  • 1. Querfurth HW, LaFerla FM (2010) Alzheimer's disease. N Engl J Med 362: 329-344.    
  • 2. 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: 479-486.
  • 3. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82: 239-259.    
  • 4. Blasko I, Stampfer-Kountchev M, Robatscher P, et al. (2004) How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes. Aging Cell 3: 169-176.    
  • 5. 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.    
  • 6. 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.    
  • 7. Hollingworth P, Harold D, Sims R, et al. (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 43: 429-435.    
  • 8. Naj AC, Jun G, Beecham GW, et al. (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet 43: 436-441.    
  • 9. Lambert JC, Heath S, Even G, et al. (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 41: 1094-1099.    
  • 10. Guerreiro R, Wojtas A, Bras J, et al. (2013) TREM2 variants in Alzheimer's disease. N Engl J Med 368: 117-127.    
  • 11. Jonsson T, Stefansson H, Steinberg S, et al. (2013) Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med 368: 107-116.    
  • 12. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45: 1452-1458.    
  • 13. 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.
  • 14. Minami SS, Min SW, Krabbe G, et al. (2014) Progranulin protects against amyloid beta deposition and toxicity in Alzheimer's disease mouse models. Nat Med 20: 1157-1164.    
  • 15. Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81: 302-313.    
  • 16. Streit WJ, Braak H, Xue QS, et al. (2009) Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta neuropathologica 118: 475-485.    
  • 17. Bauer J, Strauss S, Schreiter-Gasser U, et al. (1991) Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer's disease cortices. FEBS Lett 285: 111-114.    
  • 18. 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: 69-72.    
  • 19. Akiyama H, Ikeda K, Katoh M, et al. (1994) Expression of MRP14, 27E10, interferon-alpha and leukocyte common antigen by reactive microglia in postmortem human brain tissue. J Neuroimmunol 50: 195-201.    
  • 20. Carpenter AF, Carpenter PW, Markesbery WR (1993) Morphometric analysis of microglia in Alzheimer's disease. J Neuropathol Exp Neurol 52: 601-608.    
  • 21. Ulvestad E, Williams K, Matre R, et al. (1994) Fc receptors for IgG on cultured human microglia mediate cytotoxicity and phagocytosis of antibody-coated targets. Journal of Neuropathology & Experimental Neurology 53: 27-36.
  • 22. Colton CA, Abel C, Patchett J, et al. (1992) Lectin staining of cultured CNS microglia. J Histochem Cytochem 40: 505-512.    
  • 23. del Rio Hortega P, Penfield W (1997) Cerebral cicatrix: the reaction of neuroglia and microglia to brain wounds. Bulletin of the Johns Hopkins Hospital 41:
  • 24. Glenner GG (1979) Congophilic microangiopathy in the pathogenesis of Alzheimer's syndrome (presenile dementia). Med Hypotheses 5: 1231-1236.    
  • 25. Bahmanyar S, Higgins GA, Goldgaber D, et al. (1987) Localization of amyloid beta protein messenger RNA in brains from patients with Alzheimer's disease. Science 237: 77-80.    
  • 26. Wisniewski HM, Wegiel J, Wang KC, et al. (1989) Ultrastructural studies of the cells forming amyloid fibers in classical plaques. Can J Neurol Sci 16: 535-542.
  • 27. Wisniewski HM, Wegiel J, Wang KC, et al. (1992) Ultrastructural studies of the cells forming amyloid in the cortical vessel wall in Alzheimer's disease. Acta Neuropathol 84: 117-127.    
  • 28. Frackowiak J, Wisniewski HM, Wegiel J, et al. (1992) Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol 84:225-233.
  • 29. Prokop S, Miller KR, Heppner FL (2013) Microglia actions in Alzheimer's disease. Acta Neuropathol 126: 461-477.    
  • 30. Thal DR, Arendt T, Waldmann G, et al. (1998) Progression of neurofibrillary changes and PHF-tau in end-stage Alzheimer's disease is different from plaque and cortical microglial pathology. Neurobiol Aging 19: 517-525.    
  • 31. Xiang Z, Haroutunian V, Ho L, et al. (2006) Microglia activation in the brain as inflammatory biomarker of Alzheimer's disease neuropathology and clinical dementia. Dis Markers 22:95-102.    
  • 32. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 82: 239-259.    
  • 33. Griffin WS, Sheng JG, Roberts GW, et al. (1995) Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution. J Neuropathol Exp Neurol 54:276-281.    
  • 34. Arends YM, Duyckaerts C, Rozemuller JM, et al. (2000) Microglia, amyloid and dementia in alzheimer disease. A correlative study. Neurobiol Aging 21: 39-47.
  • 35. Sheng JG, Griffin WS, Royston MC, et al. (1998) Distribution of interleukin-1-immunoreactive microglia in cerebral cortical layers: implications for neuritic plaque formation in Alzheimer's disease. Neuropathol Appl Neurobiol 24: 278-283.    
  • 36. Sheng JG, Mrak RE, Griffin WS (1997) Neuritic plaque evolution in Alzheimer's disease is accompanied by transition of activated microglia from primed to enlarged to phagocytic forms. Acta Neuropathol 94: 1-5.    
  • 37. Fukumoto H, Asami-Odaka A, Suzuki N, et al. (1996) Association of A beta 40-positive senile plaques with microglial cells in the brains of patients with Alzheimer's disease and in non-demented aged individuals. Neurodegeneration 5: 13-17.    
  • 38. Sheng JG, Zhou XQ, Mrak RE, et al. (1998) Progressive neuronal injury associated with amyloid plaque formation in Alzheimer disease. J Neuropathol Exp Neurol 57: 714-717.    
  • 39. Troncoso JC, Sukhov RR, Kawas CH, et al. (1996) In situ labeling of dying cortical neurons in normal aging and in Alzheimer's disease: correlations with senile plaques and disease progression. J Neuropathol Exp Neurol 55: 1134-1142.    
  • 40. Rogers J, Webster S, Lue LF, et al. (1996) Inflammation and Alzheimer's disease pathogenesis. Neurobiol Aging 17: 681-686.    
  • 41. Van Den Heuvel C, Thornton E, Vink R (2007) Traumatic brain injury and Alzheimer's disease: a review. Prog Brain Res 161: 303-316.
  • 42. Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7: 161-167.    
  • 43. McGeer PL, McGeer E, Rogers J, et al. (1990) Anti-inflammatory drugs and Alzheimer disease. Lancet 335: 1037.
  • 44. McGeer EG, McGeer PL (1998) The importance of inflammatory mechanisms in Alzheimer disease. Exp Gerontol 33: 371-378.    
  • 45. Akiyama H, Barger S, Barnum S, et al. (2000) Inflammation and Alzheimer's disease. Neurobiol Aging 21: 383-421.    
  • 46. Birch AM, Katsouri L, Sastre M (2014) Modulation of inflammation in transgenic models of Alzheimer's disease. J Neuroinflammation 11: 25.    
  • 47. Colton CA, Vitek MP, Wink DA, et al. (2006) NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 103:12867-12872.    
  • 48. Kummer MP, Hermes M, Delekarte A, et al. (2011) Nitration of tyrosine 10 critically enhances amyloid beta aggregation and plaque formation. Neuron 71: 833-844.    
  • 49. 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.    
  • 50. Yamamoto M, Kiyota T, Horiba M, et al. (2007) Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 170: 680-692.    
  • 51. Shaftel SS, Kyrkanides S, Olschowka JA, et al. (2007) Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest 117: 1595-1604.    
  • 52. Matousek SB, Ghosh S, Shaftel SS, et al. (2012) Chronic IL-1beta-mediated neuroinflammation mitigates amyloid pathology in a mouse model of Alzheimer's disease without inducing overt neurodegeneration. J Neuroimmune Pharmacol 7: 156-164.    
  • 53. Jaeger LB, Dohgu S, Sultana R, et al. (2009) Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease. Brain Behav Immun 23: 507-517.    
  • 54. 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.    
  • 55. DiCarlo G, Wilcock D, Henderson D, et al. (2001) Intrahippocampal LPS injections reduce Abeta load in APP+PS1 transgenic mice. Neurobiol Aging 22: 1007-1012.    
  • 56. Herber DL, Maloney JL, Roth LM, et al. (2006) Diverse microglial responses after intrahippocampal administration of lipopolysaccharide. Glia 53: 382-391.    
  • 57. 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.    
  • 58. Qiao X, Cummins DJ, Paul SM (2001) Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur J Neurosci 14: 474-482.    
  • 59. He P, Zhong Z, Lindholm K, et al. (2007) Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice. J Cell Biol 178: 829-841.    
  • 60. Mantovani A, Sica A, Sozzani S, et al. (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25: 677-686.    
  • 61. Szekanecz Z, Koch AE (2007) Macrophages and their products in rheumatoid arthritis. Curr Opin Rheumatol 19: 289-295.    
  • 62. Edwards JP, Zhang X, Frauwirth KA, et al. (2006) Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 80: 1298-1307.    
  • 63. 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.    
  • 64. Colton CA, Mott RT, Sharpe H, et al. (2006) Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 3: 27.    
  • 65. Wilcock DM (2012) A changing perspective on the role of neuroinflammation in Alzheimer's disease. Int J Alzheimers Dis 2012: 495243.
  • 66. Wilcock DM, Zhao Q, Morgan D, et al. (2011) Diverse inflammatory responses in transgenic mouse models of Alzheimer's disease and the effect of immunotherapy on these responses. ASN Neuro 3: 249-258.    
  • 67. Weekman EM, Sudduth TL, Abner EL, et al. (2014) Transition from an M1 to a mixed neuroinflammatory phenotype increases amyloid deposition in APP/PS1 transgenic mice. J Neuroinflammation 11: 127.    
  • 68. Sudduth TL, Schmitt FA, Nelson PT, et al. (2013) Neuroinflammatory phenotype in early Alzheimer's disease. Neurobiol Aging 34: 1051-1059.    
  • 69. Perry VH (2010) Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol 120: 277-286.    
  • 70. Moreno B, Jukes JP, Vergara-Irigaray N, et al. (2011) Systemic inflammation induces axon injury during brain inflammation. Ann Neurol 70: 932-942.    
  • 71. Sudduth TL, Wilson JG, Everhart A, et al. (2012) Lithium treatment of APPSwDI/NOS2-/- mice leads to reduced hyperphosphorylated tau, increased amyloid deposition and altered inflammatory phenotype. PLoS One 7: e31993.    
  • 72. Barron KD (1995) The microglial cell. A historical review. J Neurol Sci 134 Suppl: 57-68.
  • 73. Chan WY, Kohsaka S, Rezaie P (2007) The origin and cell lineage of microglia: new concepts. Brain Res Rev 53: 344-354.    
  • 74. 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.    
  • 75. Wegiel J, Imaki H, Wang KC, et al. (2004) Cells of monocyte/microglial lineage are involved in both microvessel amyloidosis and fibrillar plaque formation in APPsw tg mice. Brain Res 1022:19-29.    
  • 76. Wegiel J, Imaki H, Wang KC, et al. (2003) Origin and turnover of microglial cells in fibrillar plaques of APPsw transgenic mice. Acta Neuropathol 105: 393-402.
  • 77. Wegiel J, Wang KC, Imaki H, et al. (2001) The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APP(SW) mice. Neurobiol Aging 22: 49-61.    
  • 78. Malm TM, Koistinaho M, Parepalo M, et al. (2005) Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol Dis 18: 134-142.    
  • 79. Simard AR, Soulet D, Gowing G, et al. (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49: 489-502.    
  • 80. Hess DC, Abe T, Hill WD, et al. (2004) Hematopoietic origin of microglial and perivascular cells in brain. Exp Neurol 186: 134-144.    
  • 81. Simard AR, Rivest S (2004) Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. FASEB J 18: 998-1000.
  • 82. Butovsky O, Koronyo-Hamaoui M, Kunis G, et al. (2006) Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci U S A 103: 11784-11789.    
  • 83. Butovsky O, Kunis G, Koronyo-Hamaoui M, et al. (2007) Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer's disease model. Eur J Neurosci 26: 413-416.    
  • 84. Calvo CF, Yoshimura T, Gelman M, et al. (1996) Production of monocyte chemotactic protein-1 by rat brain macrophages. Eur J Neurosci 8: 1725-1734.    
  • 85. Glabinski AR, Balasingam V, Tani M, et al. (1996) Chemokine monocyte chemoattractant protein-1 is expressed by astrocytes after mechanical injury to the brain. J Immunol 156:4363-4368.
  • 86. Ishizuka K, Kimura T, Igata-yi R, et al. (1997) Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer's disease. Psychiatry Clin Neurosci 51: 135-138.    
  • 87. Smits HA, Rijsmus A, van Loon JH, et al. (2002) Amyloid-beta-induced chemokine production in primary human macrophages and astrocytes. J Neuroimmunol 127: 160-168.    
  • 88. Babcock AA, Kuziel WA, Rivest S, et al. (2003) Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J Neurosci 23: 7922-7930.
  • 89. Izikson L, Klein RS, Charo IF, et al. (2000) Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. J Exp Med 192:1075-1080.    
  • 90. 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.    
  • 91. D'Mello C, Le T, Swain MG (2009) Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci 29: 2089-2102.    
  • 92. Ajami B, Bennett JL, Krieger C, et al. (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10: 1538-1543.    
  • 93. Mildner A, Schmidt H, Nitsche M, et al. (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10: 1544-1553.    
  • 94. Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19: 71-82.    
  • 95. 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.
  • 96. Xu H, Chen M, Mayer EJ, et al. (2007) Turnover of resident retinal microglia in the normal adult mouse. Glia 55: 1189-1198.    
  • 97. Lawson LJ, Perry VH, Gordon S (1992) Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48: 405-415.    
  • 98. Hua K, Schindler MK, McQuail JA, et al. (2012) Regionally distinct responses of microglia and glial progenitor cells to whole brain irradiation in adult and aging rats. PLoS One 7: e52728.    
  • 99. Long JM, Kalehua AN, Muth NJ, et al. (1998) Stereological estimation of total microglia number in mouse hippocampus. J Neurosci Methods 84: 101-108.    
  • 100. Flanary BE, Sammons NW, Nguyen C, et al. (2007) Evidence that aging and amyloid promote microglial cell senescence. Rejuvenation Res 10: 61-74.    
  • 101. Luo XG, Ding JQ, Chen SD (2010) Microglia in the aging brain: relevance to neurodegeneration. Mol Neurodegener 5: 12.    
  • 102. Streit WJ, Sammons NW, Kuhns AJ, et al. (2004) Dystrophic microglia in the aging human brain. Glia 45: 208-212.    
  • 103. Conde JR, Streit WJ (2006) Microglia in the aging brain. J Neuropathol Exp Neurol 65:199-203.    
  • 104. Flanary BE, Streit WJ (2005) Effects of axotomy on telomere length, telomerase activity, and protein in activated microglia. J Neurosci Res 82: 160-171.    
  • 105. Korotzer AR, Pike CJ, Cotman CW (1993) beta-Amyloid peptides induce degeneration of cultured rat microglia. Brain Res 624: 121-125.    
  • 106. von Bernhardi R (2007) Glial cell dysregulation: a new perspective on Alzheimer disease. Neurotox Res 12: 215-232.    
  • 107. Streit WJ, Braak H, Xue QS, et al. (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.    
  • 108. Rivera J, Tessarollo L (2008) Genetic background and the dilemma of translating mouse studies to humans. Immunity 28: 1-4.    
  • 109. van der Worp HB, Howells DW, Sena ES, et al. (2010) Can animal models of disease reliably inform human studies? PLoS Med 7: e1000245.    
  • 110. Schneemann M, Schoeden G (2007) Macrophage biology and immunology: man is not a mouse. J Leukoc Biol 81:
  • 111. Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172: 2731-2738.    
  • 112. Pound P, Ebrahim S, Sandercock P, et al. (2004) Where is the evidence that animal research benefits humans? BMJ 328: 514-517.    
  • 113. Leist M, Hartung T (2013) Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice. Arch Toxicol 87: 563-567.    
  • 114. Rice J (2012) Animal models: Not close enough. Nature 484: S9.    


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