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Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease

Molecular Psychiatry volume 11, pages 327–335 (2006)Cite this article

Abstract

The role of innate immunity and microglia in the brain is currently a matter of great debate and controversy. While several studies have provided evidence that they contribute to neurodegeneration in various animal models of brain diseases and traumas, others have shown that their inhibition may in contrast be associated with more damages or less repair. We have recently reported the existence of two different types of microglia, the resident and the newly differentiated microglia that derive from the bone marrow stem cells. Of great interest is the fact that blood-derived microglial cells are associated with amyloid plaques and these cells are able to prevent the formation or eliminate the presence of amyloid deposits in mice that develop the major hallmark of Alzheimer's disease (AD). These newly recruited cells are specifically attracted to the β-amyloid 40/42 isoforms in vivo and they participate in the elimination of these proteins by phagocytosis. This review presents the mechanisms involved in the control of the innate immune response by microglia and the beneficial properties of such a response in brain diseases, such as AD.

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References

  1. Anderson KV . Toll signaling pathways in the innate immune response. Curr Opin Immunol 2000; 12: 13–19.

    Article  CAS  PubMed  Google Scholar 

  2. Wright SD . Toll, a new piece in the puzzle of innate immunity. J Exp Med 1999; 189: 605–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nguyen MD, Julien JP, Rivest S . Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 2002; 3: 216–227.

    Article  CAS  PubMed  Google Scholar 

  4. Laflamme N, Lacroix S, Rivest S . An essential role of interleukin-1beta in mediating NF-kappaB activity and COX-2 transcription in cells of the blood–brain barrier in response to a systemic and localized inflammation but not during endotoxemia. J Neurosci 1999; 19: 10923–10930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang J, Rivest S . Is survival possible without arachidonate metabolites in the brain during systemic infection? News Physiol Sci 2003; 18: 137–142.

    Article  CAS  PubMed  Google Scholar 

  6. Glezer I, Rivest S . Glucocorticoids: protectors of the brain during innate immune responses. Neuroscientist 2004; 10: 538–552.

    Article  CAS  PubMed  Google Scholar 

  7. Tracey KJ, Cerami A . Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med 1994; 45: 491–503.

    Article  CAS  PubMed  Google Scholar 

  8. Piani D, Spranger M, Frei K, Schaffner A, Fontana A . Macrophage-induced cytotoxicity of N-methyl-D-aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines. Eur J Immunol 1992; 22: 2429–2436.

    Article  CAS  PubMed  Google Scholar 

  9. Chao CC, Hu S, Ehrlich L, Peterson PK . Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors. Brain Behav Immun 1995; 9: 355–365.

    Article  CAS  PubMed  Google Scholar 

  10. Strijbos PJ, Rothwell NJ . Interleukin-1 beta attenuates excitatory amino acid-induced neurodegeneration in vitro: involvement of nerve growth factor. J Neurosci 1995; 15: 3468–3474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Westmoreland SV, Kolson D, Gonzalez-Scarano F . Toxicity of TNF alpha and platelet activating factor for human NT2N neurons: a tissue culture model for human immunodeficiency virus dementia. J Neurovirol 1996; 2: 118–126.

    Article  CAS  PubMed  Google Scholar 

  12. Mustafa MM, Lebel MH, Ramilo O, Olsen KD, Reisch JS, Beutler B et al. Correlation of interleukin-1 beta and cachectin concentrations in cerebrospinal fluid and outcome from bacterial meningitis. J Pediatr 1989a; 115: 208–213.

    Article  CAS  PubMed  Google Scholar 

  13. Mustafa MM, Ramilo O, Olsen KD, Franklin PS, Hansen EJ, Beutler B et al. Tumor necrosis factor in mediating experimental Haemophilus influenzae type B meningitis. J Clin Invest 1989b; 84: 1253–1259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Arditi M, Manogue KR, Caplan M, Yogev R . Cerebrospinal fluid cachectin/tumor necrosis factor-alpha and platelet-activating factor concentrations and severity of bacterial meningitis in children. J Infect Dis 1990; 162: 139–147.

    Article  CAS  PubMed  Google Scholar 

  15. van Deuren M, van der Ven-Jongekrijg J, Vannier E, van Dalen R, Pesman G, Bartelink AK et al. The pattern of interleukin-1beta (IL-1beta) and its modulating agents IL-1 receptor antagonist and IL-1 soluble receptor type II in acute meningococcal infections. Blood 1997; 90: 1101–1108.

    Article  CAS  PubMed  Google Scholar 

  16. Hauser SL, Doolittle TH, Lincoln R, Brown RH, Dinarello CA . Cytokine accumulations in CSF of multiple sclerosis patients: frequent detection of interleukin-1 and tumor necrosis factor but not interleukin-6. Neurology 1990; 40: 1735–1739.

    Article  CAS  PubMed  Google Scholar 

  17. Sheng JG, Boop FA, Mrak RE, Griffin WS . Increased neuronal beta-amyloid precursor protein expression in human temporal lobe epilepsy: association with interleukin-1 alpha immunoreactivity. J Neurochem 1994; 63: 1872–1879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M, Nagatsu T . Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease. Neurosci Lett 1996; 211: 13–16.

    Article  CAS  PubMed  Google Scholar 

  19. Sriram K, Matheson JM, Benkovic SA, Miller DB, Luster MI, O'Callaghan JP . Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson's disease. FASEB J 2002; 16: 1474–1476.

    Article  CAS  PubMed  Google Scholar 

  20. Gregersen R, Lambertsen K, Finsen B . Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 2000; 20: 53–65.

    Article  CAS  PubMed  Google Scholar 

  21. Nadeau S, Rivest S . Glucocorticoids play a fundamental role in protecting the brain during innate immune response. J Neurosci 2003; 23: 5536–5544.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Stepanichev MY, Zdobnova IM, Yakovlev AA, Onufriev MV, Lazareva NA, Zarubenko II et al. Effects of tumor necrosis factor-alpha central administration on hippocampal damage in rat induced by amyloid beta-peptide (25–35). J Neurosci Res 2003; 71: 110–120.

    Article  CAS  PubMed  Google Scholar 

  23. Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK et al. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 1996; 2: 788–794.

    Article  CAS  PubMed  Google Scholar 

  24. Scherbel U, Raghupathi R, Nakamura M, Saatman KE, Trojanowski JQ, Neugebauer E et al. Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc Natl Acad Sci USA 1999; 96: 8721–8726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Probert L, Akassoglou K, Pasparakis M, Kontogeorgos G, Kollias G . Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alpha. Proc Natl Acad Sci USA 1995; 92: 11294–11298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fontaine V, Mohand-Said S, Hanoteau N, Fuchs C, Pfizenmaier K, Eisel U . Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. J Neurosci 2002; 22: RC216.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Diem R, Hobom M, Grotsch P, Kramer B, Bahr M . Interleukin-1 beta protects neurons via the interleukin-1 (IL-1) receptor-mediated Akt pathway and by IL-1 receptor-independent decrease of transmembrane currents in vivo. Mol Cell Neurosci 2003; 22: 487–500.

    Article  CAS  PubMed  Google Scholar 

  28. Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP . TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 2001; 4: 1116–1122.

    Article  CAS  PubMed  Google Scholar 

  29. Hickey WF, Kimura H . Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 1988; 239: 290–292.

    Article  CAS  PubMed  Google Scholar 

  30. Hickey WF, Vass K, Lassmann H . Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J Neuropathol Exp Neurol 1992; 51: 246–256.

    Article  CAS  PubMed  Google Scholar 

  31. Eglitis MA, Mezey E . Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 1997; 94: 4080–4085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kennedy DW, Abkowitz JL . Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model. Blood 1997; 90: 986–993.

    Article  CAS  PubMed  Google Scholar 

  33. Ono K, Takii T, Onozaki K, Ikawa M, Okabe M, Sawada M . Migration of exogenous immature hematopoietic cells into adult mouse brain parenchyma under GFP-expressing bone marrow chimera. Biochem Biophys Res Commun 1999; 262: 610–614.

    Article  CAS  PubMed  Google Scholar 

  34. Brazelton TR, Rossi FM, Keshet GI, Blau HM . From marrow to brain: expression of neuronal phenotypes in adult mice. Science 2000; 290: 1775–1779.

    Article  CAS  PubMed  Google Scholar 

  35. Nakano K, Migita M, Mochizuki H, Shimada T . Differentiation of transplanted bone marrow cells in the adult mouse brain. Transplantation 2001; 71: 1735–1740.

    Article  CAS  PubMed  Google Scholar 

  36. Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 2001a; 7: 1356–1361.

    Article  CAS  PubMed  Google Scholar 

  37. Priller J, Persons DA, Klett FF, Kempermann G, Kreutzberg GW, Dirnagl U . Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J Cell Biol 2001b; 155: 733–738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Castro RF, Jackson KA, Goodell MA, Robertson CS, Liu H, Shine HD . Failure of bone marrow cells to transdifferentiate into neural cells in vivo. Science 2002; 297: 1299.

    Article  CAS  PubMed  Google Scholar 

  39. Corti S, Locatelli F, Donadoni C, Strazzer S, Salani S, Del Bo R et al. Neuroectodermal and microglial differentiation of bone marrow cells in the mouse spinal cord and sensory ganglia. J Neurosci Res 2002; 70: 721–733.

    Article  CAS  PubMed  Google Scholar 

  40. Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003; 425: 968–973.

    Article  CAS  PubMed  Google Scholar 

  41. Vallieres L, Sawchenko PE . Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity. J Neurosci 2003; 23: 5197–5207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Weimann JM, Johansson CB, Trejo A, Blau HM . Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat Cell Biol 2003; 5: 959–966.

    Article  CAS  PubMed  Google Scholar 

  43. Simard AR, Rivest S . Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. FASEB J 2004; 18: 998–1000.

    Article  CAS  PubMed  Google Scholar 

  44. Massengale M, Wagers AJ, Vogel H, Weissman IL . Hematopoietic cells maintain hematopoietic fates upon entering the brain. J Exp Med 2005; 201: 1579–1589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tzeng SF, Wu JP . Responses of microglia and neural progenitors to mechanical brain injury. Neuroreport 1999; 10: 2287–2292.

    Article  CAS  PubMed  Google Scholar 

  46. Villeneuve J, Tremblay P, Vallieres L . Tumor necrosis factor reduces brain tumor growth by enhancing macrophage recruitment and microcyst formation. Cancer Res 2005; 65: 3928–3936.

    Article  CAS  PubMed  Google Scholar 

  47. Izikson L, Klein RS, Charo IF, Weiner HL, Luster AD . Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. J Exp Med 2000; 192: 1075–1080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tran EH, Hoekstra K, van Rooijen N, Dijkstra CD, Owens T . Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. J Immunol 1998; 161: 3767–3775.

    CAS  PubMed  Google Scholar 

  49. Walker WS . Separate precursor cells for macrophages and microglia in mouse brain: immunophenotypic and immunoregulatory properties of the progeny. J Neuroimmunol 1999; 94: 127–133.

    Article  CAS  PubMed  Google Scholar 

  50. Santambrogio L, Belyanskaya SL, Fischer FR, Cipriani B, Brosnan CF, Ricciardi-Castagnoli P et al. Developmental plasticity of CNS microglia. Proc Natl Acad Sci USA 2001; 98: 6295–6300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Monje ML, Mizumatsu S, Fike JR, Palmer TD . Irradiation induces neural precursor-cell dysfunction. Nat Med 2002; 8: 955–962.

    Article  CAS  PubMed  Google Scholar 

  52. Monje ML, Toda H, Palmer TD . Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003; 302: 1760–1765.

    Article  CAS  PubMed  Google Scholar 

  53. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O . Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA 2003; 100: 13632–13637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Vallieres L, Campbell IL, Gage FH, Sawchenko PE . Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 2002; 22: 486–492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mason JL, Suzuki K, Chaplin DD, Matsushima GK . Interleukin-1beta promotes repair of the CNS. J Neurosci 2001; 21: 7046–7052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Becher B, Durell BG, Miga AV, Hickey WF, Noelle RJ . The clinical course of experimental autoimmune encephalomyelitis and inflammation is controlled by the expression of CD40 within the central nervous system. J Exp Med 2001; 193: 967–974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Nadeau S, Rivest S . Role of microglial-derived tumor necrosis factor in mediating CD14 transcription and nuclear factor kappa B activity in the brain during endotoxemia. J Neurosci 2000; 20: 3456–3468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wilcock DM, Munireddy SK, Rosenthal A, Ugen KE, Gordon MN, Morgan D . Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiol Dis 2004; 15: 11–20.

    Article  CAS  PubMed  Google Scholar 

  59. David S, Lacroix S . Molecular approaches to spinal cord repair. Annu Rev Neurosci 2003; 26: 411–440.

    Article  CAS  PubMed  Google Scholar 

  60. Ousman SS, David S . MIP-1alpha, MCP-1, GM-CSF, and TNF-alpha control the immune cell response that mediates rapid phagocytosis of myelin from the adult mouse spinal cord. J Neurosci 2001; 21: 4649–4656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nagy Z, Esiri MM, Jobst KA, Morris JH, King EM, McDonald B et al. Relative roles of plaques and tangles in the dementia of Alzheimer's disease: correlations using three sets of neuropathological criteria. Dementia 1995; 6: 21–31.

    CAS  PubMed  Google Scholar 

  62. Berg L, McKeel Jr DW, Miller JP, Storandt M, Rubin EH, Morris JC et al. Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 1998; 55: 326–335.

    Article  CAS  PubMed  Google Scholar 

  63. Lorenzo A, Yankner BA . Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci USA 1994; 91: 12243–12247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Dickson DW, Farlo J, Davies P, Crystal H, Fuld P, Yen SH . Alzheimer's disease. A double-labeling immunohistochemical study of senile plaques. Am J Pathol 1988; 132: 86–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Haga S, Akai K, Ishii T . Demonstration of microglial cells in and around senile (neuritic) plaques in the Alzheimer brain. An immunohistochemical study using a novel monoclonal antibody. Acta Neuropathol (Berlin) 1989; 77: 569–575.

    Article  CAS  Google Scholar 

  66. Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D . Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol 1989; 24: 173–182.

    Article  CAS  PubMed  Google Scholar 

  67. Perlmutter LS, Scott SA, Barron E, Chui HC . MHC class II-positive microglia in human brain: association with Alzheimer lesions. J Neurosci Res 1992; 33: 549–558.

    Article  CAS  PubMed  Google Scholar 

  68. Sheng JG, Mrak RE, Griffin WS . Neuritic plaque evolution in Alzheimer's disease is accompanied by transition of activated microglia from primed to enlarged to phagocytic forms. Acta Neuropathol (Berlin) 1997; 94: 1–5.

    Article  CAS  Google Scholar 

  69. Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K et al. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 1998; 152: 307–317.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Wegiel J, Wang KC, Imaki H, Rubenstein R, Wronska A, Osuchowski M et al. The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APP(SW) mice. Neurobiol Aging 2001; 22: 49–61.

    Article  CAS  PubMed  Google Scholar 

  71. Wegiel J, Imaki H, Wang KC, Wronska A, Osuchowski M, Rubenstein R . Origin and turnover of microglial cells in fibrillar plaques of APPsw transgenic mice. Acta Neuropathol (Berlin) 2003; 105: 393–402.

    Article  Google Scholar 

  72. Wegiel J, Imaki H, Wang KC, Rubenstein R . Cells of monocyte/microglial lineage are involved in both microvessel amyloidosis and fibrillar plaque formation in APPsw tg mice. Brain Res 2004; 1022: 19–29.

    Article  CAS  PubMed  Google Scholar 

  73. Malm TM, Koistinaho M, Parepalo M, Vatanen T, Ooka A, Karlsson S et al. 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 2005; 18: 134–142.

    Article  CAS  PubMed  Google Scholar 

  74. Miao J, Xu F, Davis J, Otte-Holler I, Verbeek MM, Van Nostrand WE . Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol 2005; 167: 505–515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kim SU, de Vellis J . Microglia in health and disease. J Neurosci Res 2005; 81: 302–313.

    Article  CAS  PubMed  Google Scholar 

  76. Walker DG, Lue LF . Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases. J Neurosci Res 2005; 81: 412–425.

    Article  CAS  PubMed  Google Scholar 

  77. Meda L, Cassatella MA, Szendrei GI, Otvos Jr L, Baron P, Villalba M et al. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 1995; 374: 647–650.

    Article  CAS  PubMed  Google Scholar 

  78. Giulian D, Haverkamp LJ, Yu JH, Karshin W, Tom D, Li J et al. Specific domains of beta-amyloid from Alzheimer plaque elicit neuron killing in human microglia. J Neurosci 1996; 16: 6021–6037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Combs CK, Karlo JC, Kao SC, Landreth GE . beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci 2001; 21: 1179–1188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Qin L, Liu Y, Cooper C, Liu B, Wilson B, Hong JS . Microglia enhance beta-amyloid peptide-induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species. J Neurochem 2002; 83: 973–983.

    Article  CAS  PubMed  Google Scholar 

  81. Casal C, Serratosa J, Tusell JM . Relationship between beta-AP peptide aggregation and microglial activation. Brain Res 2002; 928: 76–84.

    Article  CAS  PubMed  Google Scholar 

  82. Takata K, Kitamura Y, Umeki M, Tsuchiya D, Kakimura J, Taniguchi T et al. Possible involvement of small oligomers of amyloid-beta peptides in 15-deoxy-delta 12,14 prostaglandin J2-sensitive microglial activation. J Pharmacol Sci 2003; 91: 330–333.

    Article  CAS  PubMed  Google Scholar 

  83. Hashioka S, Monji A, Ueda T, Kanba S, Nakanishi H et al. Amyloid-beta fibril formation is not necessarily required for microglial activation by the peptides. Neurochem Int 2005; 47: 369–376.

    Article  CAS  PubMed  Google Scholar 

  84. Nussbaum RL, Ellis CE . Alzheimer's disease and Parkinson's disease. N Engl J Med 2003; 348: 1356–1364.

    Article  CAS  PubMed  Google Scholar 

  85. Stewart WF, Kawas C, Corrada M, Metter EJ . Risk of Alzheimer's disease and duration of NSAID use. Neurology 1997; 48: 626–632.

    Article  CAS  PubMed  Google Scholar 

  86. Anthony JC, Breitner JC, Zandi PP, Meyer MR, Jurasova I, Norton MC et al. Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study. Neurology 2000; 54: 2066–2071.

    Article  CAS  PubMed  Google Scholar 

  87. in t' Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 2001; 345: 1515–1521.

    Article  CAS  PubMed  Google Scholar 

  88. Yip AG, Green RC, Huyck M, Cupples LA, Farrer LA . Nonsteroidal anti-inflammatory drug use and Alzheimer's disease risk: the MIRAGE Study. BMC Geriatr 2005; 5: 2.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 2003; 289: 2819–2826.

    Article  CAS  PubMed  Google Scholar 

  90. Kukar T, Murphy MP, Eriksen JL, Sagi SA, Weggen S, Smith TE et al. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production. Nat Med 2005; 11: 545–550.

    Article  CAS  PubMed  Google Scholar 

  91. Blais V, Turrin NP, Rivest S . Cyclooxygenase 2 (COX-2) inhibition increases the inflammatory response in the brain during systemic immune stimuli. J Neurochem 2005; 95: 1563–1574.

    Article  CAS  PubMed  Google Scholar 

  92. Koenigsknecht-Talboo J, Landreth GE . Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci 2005; 25: 8240–8249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shie FS, Breyer RM, Montine TJ . Microglia lacking E prostanoid receptor subtype 2 have enhanced Abeta phagocytosis yet lack Abeta-activated neurotoxicity. Am J Pathol 2005; 166: 1163–1172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Turrin NP, Rivest S . Tumor necrosis factor alpha but not interleukin 1beta mediates neuroprotection in response to acute nitric oxide excitotoxicity. J Neurosci 2006; 26: 143–151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Rogers J, Strohmeyer R, Kovelowski CJ, Li R . Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia 2002; 40: 260–269.

    Article  PubMed  Google Scholar 

  96. Rogers J, Lue LF . Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease. Neurochem Int 2001; 39: 333–340.

    Article  CAS  PubMed  Google Scholar 

  97. Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W et al. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide. Brain 2005; 128: 1778–1789.

    Article  PubMed  Google Scholar 

  98. Simard AR, Soulet D, Gowing G, Julien JP, Rivest S . Bone marrow-derived microglia play a critical role to restrict senile plaque formation in Alzheimer's disease. Neuron 2006 (in press).

  99. Korotzer AR, Pike CJ, Cotman CW beta-Amyloid peptides induce degeneration of cultured rat microglia. Brain Res 1993; 624: 121–125.

    Article  CAS  PubMed  Google Scholar 

  100. Richartz E, Stransky E, Batra A, Simon P, Lewczuk P, Buchkremer G et al. Decline of immune responsiveness: a pathogenetic factor in Alzheimer's disease? J Psychiatr Res 2005; 39: 535–543.

    Article  PubMed  Google Scholar 

  101. Streit WJ . Microglia and neuroprotection: implications for Alzheimer's disease. Brain Res Brain Res Rev 2005; 48: 234–239.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The Canadian Institutes in Health Research (CIHR) supports this research. Alain Simard is supported by a PhD. Studentship from the CIHR and Serge Rivest holds a Canadian Research Chair (Junior) in Neuroimmunology.

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  1. CHUL Research Center and Department of Anatomy and Physiology, Laboratory of Molecular Endocrinology, Laval University, QC, Canada

    A R Simard & S Rivest

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Simard, A., Rivest, S. Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease. Mol Psychiatry 11, 327–335 (2006). https://doi.org/10.1038/sj.mp.4001809

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