[en] Microglia activated by extracellularly deposited amyloid β peptide (Aβ) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing Aβ via phagocytosis. TLRs are associated with Aβ-induced microglial inflammatory activation and Aβ internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Aβ (Aβ42). TLR2 deficiency reduced Aβ42-triggered inflammatory activation but enhanced Aβ phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Aβ42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741-744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Aβ42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer's amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Aβ to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer's disease pathogenesis.
Disciplines :
Neurology
Author, co-author :
Liu, Shirong; Department of Neurology, University of the Saarland, 66421 Homburg/Saar, Germany
Liu, Yang; Department of Neurology, University of the Saarland, 66421 Homburg/Saar, Germany ; German Institute for Dementia Prevention, University of the Saarland, 66421 Homburg/Saar, Germany
Hao, Wenlin; Department of Neurology, University of the Saarland, 66421 Homburg/Saar, Germany ; German Institute for Dementia Prevention, University of the Saarland, 66421 Homburg/Saar, Germany
Wolf, Lisa; Department of Neurology, University of the Saarland, 66421 Homburg/Saar, Germany ; German Institute for Dementia Prevention, University of the Saarland, 66421 Homburg/Saar, Germany ; Department of Biotechnology, University of Applied Sciences Kaiserslautern, 66482 Zweibrücken, Germany
Kiliaan, Amanda J; Department of Anatomy, Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, Netherlands ; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, Netherlands
Penke, Botond; Department of Medical Chemistry, Albert Szent Gyorgyi Medical University, 6720 Szeged, Hungary
Rübe, Claudia E; Radiation Therapy and Radiation Oncology, University of the Saarland, 66421 Homburg/Saar, Germany
Walter, Jochen; Department of Neurology, University of Bonn, 53127 Bonn, Germany
HENEKA, Michael ; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Hartmann, Tobias; German Institute for Dementia Prevention, University of the Saarland, 66421 Homburg/Saar, Germany ; Department of Experimental Neurology, University of the Saarland, 66421 Homburg/Saar, Germany
Menger, Michael D; Institute for Clinical and Experimental Surgery, University of the Saarland, 66421 Homburg/Saar, Germany
Fassbender, Klaus; Department of Neurology, University of the Saarland, 66421 Homburg/Saar, Germany ; German Institute for Dementia Prevention, University of the Saarland, 66421 Homburg/Saar, Germany
External co-authors :
yes
Language :
English
Title :
TLR2 is a primary receptor for Alzheimer's amyloid β peptide to trigger neuroinflammatory activation.
Publication date :
01 February 2012
Journal title :
Journal of Immunology
ISSN :
0022-1767
eISSN :
1550-6606
Publisher :
The American Association of Immunologists, United States
Akiyama, H., S. Barger, S. Barnum, B. Bradt, J. Bauer, G. M. Cole, N. R. Cooper, P. Eikelenboom, M. Emmerling, B. L. Fiebich, et al. 2000. Inflammation and Alzheimer's disease. Neurobiol. Aging 21: 383-421. (Pubitemid 30349107)
Wyss-Coray, T. 2006. Inflammation in Alzheimer disease: driving force, by-stander or beneficial response? Nat. Med. 12: 1005-1015. (Pubitemid 44353380)
Cagnin, A., D. J. Brooks, A. M. Kennedy, R. N. Gunn, R. Myers, F. E. Turkheimer, T. Jones, and R. B. Banati. 2001. In-vivo measurement of activated microglia in dementia. Lancet 358: 461-467. (Pubitemid 32769854)
Edison, P., H. A. Archer, A. Gerhard, R. Hinz, N. Pavese, F. E. Turkheimer, A. Hammers, Y. F. Tai, N. Fox, A. Kennedy, et al. 2008. Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIBPET study. Neurobiol. Dis. 32: 412-419.
Okello, A., P. Edison, H. A. Archer, F. E. Turkheimer, J. Kennedy, R. Bullock, Z. Walker, A. Kennedy, N. Fox, M. Rossor, and D. J. Brooks. 2009. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology 72: 56-62.
Masters, C. L., and K. Beyreuther. 2006. Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the Abeta amyloid pathway. Brain 129: 2823-2839. (Pubitemid 44684506)
Bolmont, T., F. Haiss, D. Eicke, R. Radde, C. A. Mathis, W. E. Klunk, S. Kohsaka, M. Jucker, and M. E. Calhoun. 2008. Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J. Neurosci. 28: 4283-4292.
Meyer-Luehmann, M., T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai, and B. T. Hyman. 2008. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 451: 720-724. (Pubitemid 351220570)
Martinez, F. O., L. Helming, and S. Gordon. 2009. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27: 451-483.
Colton, C. A., R. T. Mott, H. Sharpe, Q. Xu, W. E. Van Nostrand, and M. P. Vitek. 2006. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J. Neuroinflammation 3: 27.
Town, T., V. Nikolic, and J. Tan. 2005. The microglial "activation" continuum: from innate to adaptive responses. J. Neuroinflammation 2: 24.
Butovsky, O., M. Koronyo-Hamaoui, G. Kunis, E. Ophir, G. Landa, H. Cohen, and M. Schwartz. 2006. Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc. Natl. Acad. Sci. USA 103: 11784-11789. (Pubitemid 44182528)
Ma, T. C., A. Campana, P. S. Lange, H. H. Lee, K. Banerjee, J. B. Bryson, L. Mahishi, S. Alam, R. J. Giger, S. Barnes, et al. 2010. A large-scale chemical screen for regulators of the arginase 1 promoter identifies the soy isoflavone daidzeinas a clinically approved small molecule that can promote neuronal protection or regeneration via a cAMP-independent pathway. J. Neurosci. 30: 739-748.
Sharma, S., B. Yang, X. Xi, J. C. Grotta, J. Aronowski, and S. I. Savitz. 2011. IL-10 directly protects cortical neurons by activating PI-3 kinase and STAT-3 pathways. Brain Res. 1373: 189-194.
Kuo, H. S., M. J. Tsai, M. C. Huang, C. W. Chiu, C. Y. Tsai, M. J. Lee, W. C. Huang, Y. L. Lin, W. C. Kuo, and H. Cheng. 2011. Acid fibroblast growth factor and peripheral nerve grafts regulate Th2 cytokine expression, macrophage activation, polyamine synthesis, and neurotrophin expression in transected rat spinal cords. J. Neurosci. 31: 4137-4147.
Bard, F., C. Cannon, R. Barbour, R. L. Burke, D. Games, H. Grajeda, T. Guido, K. Hu, J. Huang, K. Johnson-Wood, 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. (Pubitemid 30644751)
Liu, Y., S. Walter, M. Stagi, D. Cherny, M. Letiembre, W. Schulz-Schaeffer, H. Heine, B. Penke, H. Neumann, and K. Fassbender. 2005. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide. Brain 128: 1778-1789. (Pubitemid 41373649)
Koenigsknecht-Talboo, J., M. Meyer-Luehmann, M. Parsadanian, M. Garcia-Alloza, M. B. Finn, B. T. Hyman, B. J. Bacskai, and D. M. Holtzman. 2008. Rapid microglial response around amyloid pathology after systemic anti-Abeta antibody administration in PDAPP mice. J. Neurosci. 28: 14156-14164.
Hao, W., Y. Liu, S. Liu, S. Walter, M. O. Grimm, A. J. Kiliaan, B. Penke, T. Hartmann, C. E. Rübe, M. D. Menger, and K. Fassbender. 2011. Myeloid differentiation factor 88-deficient bone marrow cells improve Alzheimer's disease-related symptoms and pathology. Brain 134: 278-292.
Fassbender, K., S. Walter, S. Kühl, R. Landmann, K. Ishii, T. Bertsch, A. K. Stalder, F. Muehlhauser, Y. Liu, A. J. Ulmer, et al. 2004. The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J. 18: 203-205.
Walter, S., M. Letiembre, Y. Liu, H. Heine, B. Penke, W. Hao, B. Bode, N. Manietta, J. Walter, W. Schulz-Schuffer, and K. Fassbender. 2007. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell. Physiol. Biochem. 20: 947-956. (Pubitemid 350059737)
Jana, M., C. A. Palencia, and K. Pahan. 2008. Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease. J. Immunol. 181: 7254-7262.
Udan, M. L., D. Ajit, N. R. Crouse, and M. R. Nichols. 2008. Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line. J. Neurochem. 104: 524-533. (Pubitemid 350293880)
Reed-Geaghan, E. G., J. C. Savage, A. G. Hise, and G. E. Landreth. 2009. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J. Neurosci. 29: 11982-11992.
Reed-Geaghan, E. G., Q. W. Reed, P. E. Cramer, and G. E. Landreth. 2010. Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu. J. Neurosci. 30: 15369-15373.
Richard, K. L., M. Filali, P. Préfontaine, and S. Rivest. 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.
Tahara, K., H. D. Kim, J. J. Jin, J. A. Maxwell, L. Li, and K. Fukuchi. 2006. Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 129: 3006-3019. (Pubitemid 44684521)
Lim, J. E., J. Kou, M. Song, A. Pattanayak, J. Jin, R. Lalonde, and K. Fukuchi. 2011. MyD88 deficiency ameliorates b-amyloidosis in an animal model of Alzheimer's disease. Am. J. Pathol. 179: 1095-1103.
Jankowsky, J. L., H. H. Slunt, T. Ratovitski, N. A. Jenkins, N. G. Copeland, and D. R. Borchelt. 2001. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol. Eng. 17: 157-165. (Pubitemid 32409891)
Dahlgren, K. N., A. M. Manelli, W. B. Stine, Jr., L. K. Baker, G. A. Krafft, and M. J. LaDu. 2002. Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J. Biol. Chem. 277: 32046-32053. (Pubitemid 34969015)
Tu, Y., S. Wu, X. Shi, K. Chen, and C. Wu. 2003. Migfilin and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation. Cell 113: 37-47. (Pubitemid 36411958)
O'Leary, T. P., and R. E. Brown. 2009. Visuo-spatial learning and memory deficits on the Barnes maze in the 16-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease. Behav. Brain Res. 201: 120-127.
Pham, E., L. Crews, K. Ubhi, L. Hansen, A. Adame, A. Cartier, D. Salmon, D. Galasko, S. Michael, J. N. Savas, et al. 2010. Progressive accumulation of amyloid-b oligomers in Alzheimer's disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins. FEBS J. 277: 3051-3067.
Priller, J., A. Flügel, T. Wehner, M. Boentert, C. A. Haas, M. Prinz, F. Fernández-Klett, K. Prass, I. Bechmann, B. A. de Boer, et al. 2001. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat. Med. 7: 1356-1361. (Pubitemid 34007942)
Brightbill, H. D., D. H. Libraty, S. R. Krutzik, R. B. Yang, J. T. Belisle, J. R. Bleharski, M. Maitland, M. V. Norgard, S. E. Plevy, S. T. Smale, et al. 1999. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285: 732-736.
Medzhitov, R., and C. A. Janeway, Jr. 1997. Innate immunity: the virtues of a nonclonal system of recognition. Cell 91: 295-298. (Pubitemid 27467959)
Jin, M. S., and J. O. Lee. 2008. Structures of the toll-like receptor family and its ligand complexes. Immunity 29: 182-191.
Gautam, J. K., Ashish, L. D. Comeau, J. K. Krueger, and M. F. Smith Jr. 2006. Structural and functional evidence for the role of the TLR2 DD loop in TLR1/TLR2 heterodimerization and signaling. J. Biol. Chem. 281: 30132-30142. (Pubitemid 44537021)
Keene, C. D., R. C. Chang, A. H. Lopez-Yglesias, B. R. Shalloway, I. Sokal, X. Li, P. J. Reed, L. M. Keene, K. S. Montine, R. M. Breyer, 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.
Park, J. H., G. A.Widi, D. A. Gimbel, N. Y. Harel, D. H. Lee, and S.M. Strittmatter. 2006. Subcutaneous Nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer's transgenic mice. J. Neurosci. 26: 13279-13286. (Pubitemid 46011638)
Kajava, A. V., and T. Vasselon. 2010. A network of hydrogen bonds on the surface of TLR2 controls ligand positioning and cell signaling. J. Biol. Chem. 285: 6227-6234.
Farhat, K., S. Riekenberg, H. Heine, J. Debarry, R. Lang, J. Mages, U. Buwitt-Beckmann, K. Röschmann, G. Jung, K. H. Wiesmüller, and A. J. Ulmer. 2008. Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling. J. Leukoc. Biol. 83: 692-701. (Pubitemid 351966879)
Tschirren, B., L. Råberg, and H.Westerdahl. 2011. Signatures of selection acting on the innate immunity gene Toll-like receptor 2 (TLR2) during the evolutionary history of rodents. J. Evol. Biol. 24: 1232-1240.
Babcock, A. A., H. Toft-Hansen, and T. Owens. 2008. Signaling through MyD88 regulates leukocyte recruitment after brain injury. J. Immunol. 181: 6481-6490.
Mildner, A., B. Schlevogt, K. Kierdorf, C. Böttcher, D. Erny, M. P. Kummer, M. Quinn, W. Brück, I. Bechmann, M. T. Heneka, et al. 2011. Distinct and nonredundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J. Neurosci. 31: 11159-11171.
Rolls, A., R. Shechter, A. London, Y. Ziv, A. Ronen, R. Levy, and M. Schwartz. 2007. Toll-like receptors modulate adult hippocampal neurogenesis. Nat. Cell Biol. 9: 1081-1088. (Pubitemid 47338146)
Babcock, A. A., M. Wirenfeldt, T. Holm, H. H. Nielsen, L. Dissing-Olesen, H. Toft-Hansen, J. M. Millward, R. Landmann, S. Rivest, B. Finsen, and T. Owens. 2006. Toll-like receptor 2 signaling in response to brain injury: an innate bridge to neuroinflammation. J. Neurosci. 26: 12826-12837. (Pubitemid 44904578)
Jimenez, S., D. Baglietto-Vargas, C. Caballero, I. Moreno-Gonzalez, M. Torres, R. Sanchez-Varo, D. Ruano, M. Vizuete, A. Gutierrez, and J. Vitorica. 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.
Simard, A. R., D. Soulet, G. Gowing, J. P. Julien, and S. Rivest. 2006. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49: 489-502. (Pubitemid 43221886)
Grathwohl, S. A., R. E. Kälin, T. Bolmont, S. Prokop, G. Winkelmann, S. A. Kaeser, J. Odenthal, R. Radde, T. Eldh, S. Gandy, et al. 2009. Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci. 12: 1361-1363.
