Home LiteratureArticle Details
PMID: 19688332 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Toll-like receptors in Alzheimer's disease.

Current topics in microbiology and immunology ·Vol. 336 ·2009-00-00 ·Pages 137-53

Landreth GE, Reed-Geaghan EG

Abstract

Alzheimer's disease (AD) is characterized by the formation of insoluble deposits of beta-amyloid (Abeta) within the parenchyma of the brain. These deposits are associated with a robust microglia-mediated inflammatory response. Recent work has demonstrated that Toll-like receptors (TLRs) participate in this inflammatory response. This chapter reviews the mechanisms whereby TLRs contribute to the induction of a microglial inflammatory response to promote AD pathogenesis. Specifically, the involvement of CD14 and the TLRs in microglial activation is delineated. The TLR-mediated microglial response has beneficial roles in stimulating phagocytosis as well as detrimental roles in the Abeta-stimulated release of neurotoxic products.

MeSH Terms
Alzheimer Disease/immunology Amyloid beta-Peptides/immunology Humans Toll-Like Receptors/immunology
Chemicals
Amyloid beta-Peptides Toll-Like Receptors
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Landreth Gary E
Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA, gel2@case.edu
Reed-Geaghan Erin G
References (89)
89 references, click to expand
  1. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines.
    J Neurosci. 2005 Sep 7;25(36):8240-9 PMID: 16148231
  2. Neuronal control of the immune response in the central nervous system: linking brain immunity to neurodegeneration.
    J Neuropathol Exp Neurol. 1998 Jan;57(1):1-9 PMID: 9600191
  3. Amyloid beta peptide 1-40 enhances the action of Toll-like receptor-2 and -4 agonists but antagonizes Toll-like receptor-9-induced inflammation in primary mouse microglial cell cultures.
    J Neurochem. 2005 Jul;94(2):289-98 PMID: 15998280
  4. Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor.
    J Immunol. 2004 Jun 1;172(11):7078-85 PMID: 15153530
  5. Interaction between CD14 and LXRbeta genes modulates Alzheimer's disease risk.
    J Neurol Sci. 2008 Jan 15;264(1-2):97-9 PMID: 17900622
  6. NF-kappaB activation through IKK-i-dependent I-TRAF/TANK phosphorylation.
    Genes Cells. 2000 Mar;5(3):191-202 PMID: 10759890
  7. Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors.
    J Endotoxin Res. 2007;13(1):6-14 PMID: 17621541
  8. Role of toll-like receptor signalling in Abeta uptake and clearance.
    Brain. 2006 Nov;129(Pt 11):3006-19 PMID: 16984903
  9. Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin.
    Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12849-54 PMID: 17652175
  10. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation.
    Nat Immunol. 2004 May;5(5):503-7 PMID: 15064760
  11. Immune system response in Alzheimer's disease.
    Can J Neurol Sci. 1989 Nov;16(4 Suppl):516-27 PMID: 2804814
  12. Systemic inflammatory markers and risk of dementia.
    Am J Alzheimers Dis Other Demen. 2006 Aug-Sep;21(4):258-62 PMID: 16948290
  13. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo.
    Genes Dev. 2005 Nov 15;19(22):2668-81 PMID: 16260493
  14. Signaling to NF-kappaB by Toll-like receptors.
    Trends Mol Med. 2007 Nov;13(11):460-9 PMID: 18029230
  15. Inflammation and Alzheimer's disease.
    Neurobiol Aging. 2000 May-Jun;21(3):383-421 PMID: 10858586
  16. NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase.
    EMBO J. 1999 Dec 1;18(23):6694-704 PMID: 10581243
  17. Microglia: active sensor and versatile effector cells in the normal and pathologic brain.
    Nat Neurosci. 2007 Nov;10(11):1387-94 PMID: 17965659
  18. Prevention of Alzheimer's disease and dementia. Major findings from the Kungsholmen Project.
    Physiol Behav. 2007 Sep 10;92(1-2):98-104 PMID: 17588621
  19. Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism.
    J Neurosci. 2004 Nov 3;24(44):9838-46 PMID: 15525768
  20. The LPS receptor (CD14) links innate immunity with Alzheimer's disease.
    FASEB J. 2004 Jan;18(1):203-5 PMID: 14597556
  21. Risk of Alzheimer's disease and duration of NSAID use.
    Neurology. 1997 Mar;48(3):626-32 PMID: 9065537
  22. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide.
    Brain. 2005 Aug;128(Pt 8):1778-89 PMID: 15857927
  23. Toll-like receptors and innate immunity.
    Nat Rev Immunol. 2001 Nov;1(2):135-45 PMID: 11905821
  24. Immune system associated antigens expressed by cells of the human central nervous system.
    Neurosci Lett. 1988 Nov 22;94(1-2):17-22 PMID: 3266526
  25. Nonsteroidal anti-inflammatory drugs in Alzheimer's disease.
    Neurology. 1995 Jan;45(1):51-5 PMID: 7824134
  26. Limiting inflammatory responses during activation of innate immunity.
    Nat Immunol. 2005 Dec;6(12):1198-205 PMID: 16369559
  27. Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta.
    Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3533-8 PMID: 14982987
  28. Ubiquitin-mediated activation of TAK1 and IKK.
    Oncogene. 2007 May 14;26(22):3214-26 PMID: 17496917
  29. 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
  30. Screening of innate immune receptors in neurodegenerative diseases: a similar pattern.
    Neurobiol Aging. 2009 May;30(5):759-68 PMID: 17905482
  31. Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer's disease.
    Drugs Aging. 2003;20(2):101-13 PMID: 12534311
  32. CpG-containing oligodeoxynucleotide promotes microglial cell uptake of amyloid beta 1-42 peptide by up-regulating the expression of the G-protein- coupled receptor mFPR2.
    FASEB J. 2005 Dec;19(14):2032-4 PMID: 16219804
  33. Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation.
    J Biol Chem. 2005 Nov 4;280(44):36560-6 PMID: 16115877
  34. Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance.
    J Neurosci. 2008 Apr 16;28(16):4283-92 PMID: 18417708
  35. Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease.
    J Immunol. 2008 Nov 15;181(10):7254-62 PMID: 18981147
  36. Alternative activation of macrophages.
    Nat Rev Immunol. 2003 Jan;3(1):23-35 PMID: 12511873
  37. TAB2 is essential for prevention of apoptosis in fetal liver but not for interleukin-1 signaling.
    Mol Cell Biol. 2003 Feb;23(4):1231-8 PMID: 12556483
  38. Molecular, cellular, and pathologic characterization of HLA-DR immunoreactivity in normal elderly and Alzheimer's disease brain.
    Exp Neurol. 1990 Oct;110(1):93-104 PMID: 1698655
  39. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice.
    J Neurosci. 2008 Aug 13;28(33):8354-60 PMID: 18701698
  40. Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide.
    J Biol Chem. 2006 Feb 10;281(6):3651-9 PMID: 16339765
  41. Other functions, other genes: alternative activation of antigen-presenting cells.
    Immunity. 1999 Feb;10(2):137-42 PMID: 10072066
  42. TAK1 is a ubiquitin-dependent kinase of MKK and IKK.
    Nature. 2001 Jul 19;412(6844):346-51 PMID: 11460167
  43. Clinical trial of indomethacin in Alzheimer's disease.
    Neurology. 1993 Aug;43(8):1609-11 PMID: 8351023
  44. Role of formyl peptide receptor-like 1 (FPRL1/FPR2) in mononuclear phagocyte responses in Alzheimer disease.
    Immunol Res. 2005;31(3):165-76 PMID: 15888909
  45. Demonstration of microglial cells in and around senile (neuritic) plaques in the Alzheimer brain. An immunohistochemical study using a novel monoclonal antibody.
    Acta Neuropathol. 1989;77(6):569-75 PMID: 2750476
  46. Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia.
    FASEB J. 2004 Jun;18(9):998-1000 PMID: 15084516
  47. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling.
    J Immunol. 2002 Dec 15;169(12):6668-72 PMID: 12471095
  48. Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors.
    Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10601-6 PMID: 17563384
  49. Regulation of phagosome maturation by signals from toll-like receptors.
    Science. 2004 May 14;304(5673):1014-8 PMID: 15143282
  50. 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
  51. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.
    Trends Immunol. 2002 Nov;23(11):549-55 PMID: 12401408
  52. beta-Amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes.
    J Neurosci. 1998 Jun 15;18(12):4451-60 PMID: 9614222
  53. Finding NEMO by K63-linked polyubiquitin chain.
    Cell Death Differ. 2006 Nov;13(11):1835-8 PMID: 16858426
  54. Activation of p38 in stimulated human neutrophils: phosphorylation of the oxidase component p47phox by p38 and ERK but not by JNK.
    Arch Biochem Biophys. 1996 Oct 15;334(2):395-400 PMID: 8900416
  55. Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease.
    Neurosci Lett. 2006 Jan 2;391(3):147-9 PMID: 16157451
  56. The role of amyloid beta peptide 42 in Alzheimer's disease.
    Pharmacol Ther. 2007 Nov;116(2):266-86 PMID: 17716740
  57. Microgliosis: the questions shape the answers.
    Nat Neurosci. 2007 Dec;10(12):1507-9 PMID: 18043584
  58. Fibrillar beta-amyloid-stimulated intracellular signaling cascades require Vav for induction of respiratory burst and phagocytosis in monocytes and microglia.
    J Biol Chem. 2006 Jul 28;281(30):20842-20850 PMID: 16728400
  59. Abeta-induced inflammatory processes in microglia cells of APP23 transgenic mice.
    Am J Pathol. 2001 Jan;158(1):63-73 PMID: 11141480
  60. Triggering the interferon antiviral response through an IKK-related pathway.
    Science. 2003 May 16;300(5622):1148-51 PMID: 12702806
  61. Prostaglandin D2 mediates neuronal damage by amyloid-beta or prions which activates microglial cells.
    Neuropharmacology. 2006 Feb;50(2):229-37 PMID: 16289250
  62. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation.
    J Neurosci. 2003 Apr 1;23(7):2665-74 PMID: 12684452
  63. Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling.
    J Immunol. 2003 Oct 15;171(8):4304-10 PMID: 14530355
  64. 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
  65. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease.
    Cell Physiol Biochem. 2007;20(6):947-56 PMID: 17982277
  66. Toward a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein.
    Ann N Y Acad Sci. 2000;924:17-25 PMID: 11193794
  67. The origin and cell lineage of microglia: new concepts.
    Brain Res Rev. 2007 Feb;53(2):344-54 PMID: 17188751
  68. ATP mediates rapid microglial response to local brain injury in vivo.
    Nat Neurosci. 2005 Jun;8(6):752-8 PMID: 15895084
  69. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease.
    J Neuroinflammation. 2005 Mar 11;2(1):9 PMID: 15762998
  70. Innate immune receptor expression in normal brain aging.
    Neuroscience. 2007 Apr 25;146(1):248-54 PMID: 17293054
  71. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans.
    Nat Genet. 2000 Jun;25(2):187-91 PMID: 10835634
  72. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease.
    Neurobiol Aging. 1988 Jul-Aug;9(4):339-49 PMID: 3263583
  73. The role of A beta 42 in Alzheimer's disease.
    J Physiol Paris. 1998 Jun-Aug;92(3-4):289-92 PMID: 9789825
  74. 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. 2008 May 28;28(22):5784-93 PMID: 18509040
  75. Toll-like receptors in central nervous system glial inflammation and homeostasis.
    J Neurosci Res. 2006 Apr;83(5):711-30 PMID: 16541438
  76. Potential role of the formyl peptide receptor-like 1 (FPRL1) in inflammatory aspects of Alzheimer's disease.
    J Leukoc Biol. 2002 Oct;72(4):628-35 PMID: 12377930
  77. Inflamm-aging. An evolutionary perspective on immunosenescence.
    Ann N Y Acad Sci. 2000 Jun;908:244-54 PMID: 10911963
  78. Risk factors for vascular dementia and Alzheimer disease.
    Stroke. 2004 Nov;35(11 Suppl 1):2620-2 PMID: 15375299
  79. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses.
    Nat Rev Immunol. 2004 Jun;4(6):469-78 PMID: 15173835
  80. Beta amyloid peptide (Abeta42) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages.
    FASEB J. 2001 Nov;15(13):2454-62 PMID: 11689470
  81. Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line.
    J Neurochem. 2008 Jan;104(2):524-33 PMID: 17986235
  82. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.
    Science. 1998 Dec 11;282(5396):2085-8 PMID: 9851930
  83. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease.
    J Neuroinflammation. 2008 May 29;5:23 PMID: 18510752
  84. Mechanisms of A beta mediated neurodegeneration in Alzheimer's disease.
    Int J Biochem Cell Biol. 2008;40(2):181-98 PMID: 17804276
  85. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo.
    Science. 2005 May 27;308(5726):1314-8 PMID: 15831717
  86. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase.
    Hum Mol Genet. 2004 Jan 15;13(2):159-70 PMID: 14645205
  87. Microglia kill amyloid-beta1-42 damaged neurons by a CD14-dependent process.
    Neuroreport. 2004 Jun 28;15(9):1427-30 PMID: 15194867
  88. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.
    Nat Immunol. 2003 May;4(5):491-6 PMID: 12692549
  89. Amyloid-beta induces chemotaxis and oxidant stress by acting at formylpeptide receptor 2, a G protein-coupled receptor expressed in phagocytes and brain.
    J Biol Chem. 2001 Jun 29;276(26):23645-52 PMID: 11316806
Article Info
Journal
Current topics in microbiology and immunology
Abbr.
Curr Top Microbiol Immunol
ISSN
0070-217X
DOI
10.1007/978-3-642-00549-7_8
Email
gel2@case.edu
Published
2009-00-00
Pages
137-53
Language
English
Region
Germany
NLM ID
0110513
PMCID
PMC3032986
Subset
IM
Grants
NINDS NIH HHS · F31 NS057867 · United States
NINDS NIH HHS · F31 NS057867-02 · United States
NIA NIH HHS · AG16047 · United States
NINDS NIH HHS · F31NS057867 · United States
External Links
PubMed source DOI: 10.1007/978-3-642-00549-7_8 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2