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PMID: 16148231 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 25 ·No. 36 ·2005-09-07 ·Pages 8240-9

Koenigsknecht-Talboo J, Landreth GE

Abstract

Microglia undergo a phenotypic activation in response to fibrillar beta-amyloid (fAbeta) deposition in the brains of Alzheimer's disease (AD) patients, resulting in their elaboration of inflammatory molecules. Despite the presence of abundant plaque-associated microglia in the brains of AD patients and in animal models of the disease, microglia fail to efficiently clear fAbeta deposits. However, they can be induced to do so during Abeta vaccination therapy attributable to anti-Abeta antibody stimulation of IgG receptor (FcR)-mediated phagocytic clearance of Abeta plaques. We report that proinflammatory cytokines attenuate microglial phagocytosis stimulated by fAbeta or complement receptor 3 and argue that this may, in part, underlie the accumulation of fAbeta-containing plaques within the AD brain. The proinflammatory suppression of fAbeta-elicited phagocytosis is dependent on nuclear factor kappaB activation. Significantly, the proinflammatory cytokines do not inhibit phagocytosis elicited by antibody-mediated activation of FcR, which may contribute to the efficiency of Abeta vaccination-based therapy. Importantly, the proinflammatory suppression of fAbeta phagocytosis can be relieved by the coincubation with anti-inflammatory cytokines, cyclooxygenase inhibitors, ibuprofen, or an E prostanoid receptor antagonist, suggesting that proinflammatory cytokines induce the production of prostaglandins, leading to an E prostanoid receptor-dependent inhibition of phagocytosis. These findings support anti-inflammatory therapies for the treatment of AD.

MeSH Terms
Amyloid beta-Peptides/pharmacology Animals Animals, Newborn Cytokines/pharmacology Electric Stimulation Immunoglobulin G/pharmacology Inflammation Interleukin-1/pharmacology Interleukins/pharmacology Mice Mice, Inbred C57BL Microglia/drug effects,physiology Peptide Fragments/pharmacology Phagocytosis/drug effects,physiology Transforming Growth Factor beta/pharmacology
Chemicals
Amyloid beta-Peptides Cytokines Immunoglobulin G Interleukin-1 Interleukins Peptide Fragments Transforming Growth Factor beta amyloid beta-protein (1-42) amyloid beta-protein (25-35)
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Koenigsknecht-Talboo Jessica
Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Landreth Gary E
References (81)
81 references, click to expand
  1. Other functions, other genes: alternative activation of antigen-presenting cells.
    Immunity. 1999 Feb;10(2):137-42 PMID: 10072066
  2. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
    Nature. 1999 Jul 8;400(6740):173-7 PMID: 10408445
  3. Regional distribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease.
    J Neurosci Res. 1999 Aug 1;57(3):295-303 PMID: 10412020
  4. Prostanoid receptors: structures, properties, and functions.
    Physiol Rev. 1999 Oct;79(4):1193-226 PMID: 10508233
  5. The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex.
    J Immunol. 1999 Nov 15;163(10):5617-23 PMID: 10553091
  6. Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation.
    Science. 1999 Dec 17;286(5448):2352-5 PMID: 10600748
  7. Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists.
    J Neurosci. 2000 Jan 15;20(2):558-67 PMID: 10632585
  8. A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study.
    Neurology. 2000 Feb 8;54(3):588-93 PMID: 10680787
  9. Regulation of macrophage gene expression by pro- and anti-inflammatory cytokines.
    Pathobiology. 1999;67(5-6):241-4 PMID: 10725793
  10. Inflammation and Alzheimer's disease.
    Neurobiol Aging. 2000 May-Jun;21(3):383-421 PMID: 10858586
  11. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease.
    J Neurosci. 2000 Aug 1;20(15):5709-14 PMID: 10908610
  12. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.
    Nat Med. 2000 Aug;6(8):916-9 PMID: 10932230
  13. NF-kappaB: a key role in inflammatory diseases.
    J Clin Invest. 2001 Jan;107(1):7-11 PMID: 11134171
  14. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease.
    Nature. 2000 Dec 21-28;408(6815):982-5 PMID: 11140686
  15. beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis.
    J Neurosci. 2001 Feb 15;21(4):1179-88 PMID: 11160388
  16. Effect of anti-inflammatory medications on neuropathological findings in Alzheimer disease.
    Arch Neurol. 2001 Mar;58(3):517-9 PMID: 11255462
  17. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice.
    Nat Med. 2001 May;7(5):612-8 PMID: 11329064
  18. 3D-Reconstruction of microglia and amyloid in APP23 transgenic mice: no evidence of intracellular amyloid.
    Neurobiol Aging. 2001 May-Jun;22(3):427-34 PMID: 11378249
  19. Immunological aspects of alzheimer's disease: therapeutic implications.
    BioDrugs. 2001;15(5):325-37 PMID: 11437695
  20. Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse.
    Eur J Neurosci. 2001 Aug;14(3):474-82 PMID: 11553297
  21. Cyclooxygenase-independent actions of cyclooxygenase inhibitors.
    FASEB J. 2001 Oct;15(12):2057-72 PMID: 11641233
  22. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity.
    Nature. 2001 Nov 8;414(6860):212-6 PMID: 11700559
  23. Behavioral assessment of Alzheimer's transgenic mice following long-term Abeta vaccination: task specificity and correlations between Abeta deposition and spatial memory.
    DNA Cell Biol. 2001 Nov;20(11):737-44 PMID: 11788052
  24. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease.
    N Engl J Med. 2001 Nov 22;345(21):1515-21 PMID: 11794217
  25. Microglial activation and beta -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice.
    J Neurosci. 2002 Mar 15;22(6):2246-54 PMID: 11896164
  26. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice.
    Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10837-42 PMID: 12119423
  27. CD40-CD40L interaction in Alzheimer's disease.
    Curr Opin Pharmacol. 2002 Aug;2(4):445-51 PMID: 12127879
  28. Suppressor of cytokine signaling 1 inhibits cytokine induction of CD40 expression in macrophages.
    J Immunol. 2002 Sep 1;169(5):2354-60 PMID: 12193701
  29. Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy.
    J Neurosci. 2002 Sep 15;22(18):7873-8 PMID: 12223540
  30. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.
    Trends Immunol. 2002 Nov;23(11):549-55 PMID: 12401408
  31. Alternative activation of macrophages.
    Nat Rev Immunol. 2003 Jan;3(1):23-35 PMID: 12511873
  32. The inflammatory macrophage: a story of Jekyll and Hyde.
    Clin Sci (Lond). 2003 Jan;104(1):27-38 PMID: 12519085
  33. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ.
    Nat Med. 2003 Apr;9(4):453-7 PMID: 12612547
  34. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation.
    J Neurosci. 2003 Apr 1;23(7):2665-74 PMID: 12684452
  35. Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation.
    J Neurosci. 2003 May 1;23(9):3745-51 PMID: 12736345
  36. Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease.
    Neuron. 2003 May 22;38(4):547-54 PMID: 12765607
  37. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial.
    JAMA. 2003 Jun 4;289(21):2819-26 PMID: 12783912
  38. The non-cyclooxygenase targets of non-steroidal anti-inflammatory drugs, lipoxygenases, peroxisome proliferator-activated receptor, inhibitor of kappa B kinase, and NF kappa B, do not reduce amyloid beta 42 production.
    J Biol Chem. 2003 Aug 22;278(34):31825-30 PMID: 12805355
  39. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization.
    Neurology. 2003 Jul 8;61(1):46-54 PMID: 12847155
  40. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease.
    J Neurosci. 2003 Aug 20;23(20):7504-9 PMID: 12930788
  41. Novel regulatory mechanisms of CD40-induced prostanoid synthesis by IL-4 and IL-10 in human monocytes.
    J Immunol. 2004 Feb 15;172(4):2147-54 PMID: 14764680
  42. Clearing amyloid through the blood-brain barrier.
    J Neurochem. 2004 May;89(4):807-11 PMID: 15140180
  43. Prostaglandin E2 regulates amyloid precursor protein expression via the EP2 receptor in cultured rat microglia.
    Neurosci Lett. 2004 May 20;362(2):127-30 PMID: 15193769
  44. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides.
    Nat Med. 2004 Jul;10(7):719-26 PMID: 15195085
  45. Prostaglandin E2 inhibits alveolar macrophage phagocytosis through an E-prostanoid 2 receptor-mediated increase in intracellular cyclic AMP.
    J Immunol. 2004 Jul 1;173(1):559-65 PMID: 15210817
  46. Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition.
    J Neurosci. 2004 Jul 7;24(27):6144-51 PMID: 15240806
  47. Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism.
    J Neurosci. 2004 Nov 3;24(44):9838-46 PMID: 15525768
  48. Lifelong immunization with human beta-amyloid (1-42) protects Alzheimer's transgenic mice against cognitive impairment throughout aging.
    Neuroscience. 2005;130(3):667-84 PMID: 15590151
  49. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD.
    Neurology. 2005 Jan 11;64(1):94-101 PMID: 15642910
  50. CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid beta-peptide.
    Eur J Immunol. 2005 Mar;35(3):901-10 PMID: 15688347
  51. Inhibition of human neuroblastoma cell growth by CAY10404, a highly selective Cox-2 inhibitor.
    J Neurooncol. 2005 Jan;71(2):141-8 PMID: 15690129
  52. An immortalized cell line expresses properties of activated microglial cells.
    J Neurosci Res. 1992 Apr;31(4):616-21 PMID: 1578513
  53. Microglia lacking E Prostanoid Receptor subtype 2 have enhanced Abeta phagocytosis yet lack Abeta-activated neurotoxicity.
    Am J Pathol. 2005 Apr;166(4):1163-72 PMID: 15793296
  54. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo.
    Science. 2005 May 27;308(5726):1314-8 PMID: 15831717
  55. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production.
    Nat Med. 2005 May;11(5):545-50 PMID: 15834426
  56. Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs.
    J Biol Chem. 1992 Jan 5;267(1):546-54 PMID: 1730616
  57. Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus.
    J Neuroimmunol. 1990 May;27(2-3):229-37 PMID: 2110186
  58. Prostaglandin-mediated suppression of macrophage phagocytosis of Listeria monocytogenes.
    Cell Immunol. 1987 Nov;110(1):68-76 PMID: 3119229
  59. Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence.
    J Biol Chem. 1995 Jun 16;270(24):14255-8 PMID: 7782278
  60. Nonsteroidal anti-inflammatory drugs in Alzheimer's disease.
    Neurology. 1995 Jan;45(1):51-5 PMID: 7824134
  61. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red.
    Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12243-7 PMID: 7991613
  62. Alzheimer beta-amyloid peptide 25-35: electrostatic interactions with phospholipid membranes.
    Biochemistry. 1994 Jun 14;33(23):7434-41 PMID: 8003508
  63. Clinical trial of indomethacin in Alzheimer's disease.
    Neurology. 1993 Aug;43(8):1609-11 PMID: 8351023
  64. The NF-kappa B and I kappa B proteins: new discoveries and insights.
    Annu Rev Immunol. 1996;14:649-83 PMID: 8717528
  65. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies.
    Neurology. 1996 Aug;47(2):425-32 PMID: 8757015
  66. Molecular mechanisms of microglial activation.
    Adv Neuroimmunol. 1996;6(2):191-22 PMID: 8876774
  67. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs.
    J Biol Chem. 1997 Feb 7;272(6):3406-10 PMID: 9013583
  68. Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia.
    J Neurosci. 1997 Apr 1;17(7):2284-94 PMID: 9065490
  69. Risk of Alzheimer's disease and duration of NSAID use.
    Neurology. 1997 Mar;48(3):626-32 PMID: 9065537
  70. Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer's disease.
    Psychiatry Clin Neurosci. 1997 Jun;51(3):135-8 PMID: 9225377
  71. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation.
    Nature. 1998 Jan 1;391(6662):79-82 PMID: 9422508
  72. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.
    Nature. 1998 Jan 1;391(6662):82-6 PMID: 9422509
  73. Regulation of macrophage phagocytosis of apoptotic cells by cAMP.
    J Immunol. 1998 Apr 1;160(7):3562-8 PMID: 9531319
  74. Mechanism of action of antiinflammatory drugs.
    Int J Tissue React. 1998;20(1):3-15 PMID: 9561441
  75. Cyclooxygenases 1 and 2.
    Annu Rev Pharmacol Toxicol. 1998;38:97-120 PMID: 9597150
  76. Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer's disease brain.
    Neuroscience. 1998 Nov;87(2):319-24 PMID: 9740394
  77. Pharmacological analysis of cyclooxygenase-1 in inflammation.
    Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13313-8 PMID: 9789085
  78. Alzheimer's beta-amyloid peptide 1-42 induces a phagocytic response in murine microglia.
    J Neurochem. 1998 Nov;71(5):2123-31 PMID: 9798938
  79. Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases.
    Science. 1998 Nov 27;282(5394):1717-21 PMID: 9831565
  80. Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins.
    J Neurosci. 1999 Feb 1;19(3):928-39 PMID: 9920656
  81. Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer's disease brains.
    Biochem Biophys Res Commun. 1999 Jan 27;254(3):582-6 PMID: 9920782
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1808-05.2005
Published
2005-09-07
Pages
8240-9
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6725530
Subset
IM
Grants
NIA NIH HHS · R01 AG020202 · United States
NIA NIH HHS · AG20202 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.1808-05.2005 PMC Full Text View journal details
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