[en] The hypothesis that accumulation of beta-amyloid (Aβ) species in the brain represents a major event in Alzheimer's disease (AD) pathogenesis still prevails; nevertheless, an array of additional pathological processes contributes to clinical presentation and disease progression. We sought to identify novel targets for AD within genes related to amyloid precursor protein (APP) processing, innate immune responses, and the catecholamine system. Through a series of bioinformatics analyses, we identified TLR5 and other genes involved in toll-like receptor (TLR) signaling as potential AD targets. It is believed that Aβ species induce activation of microglia and astrocytes in AD, with a negative impact on disease progression. The TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases plays pivotal roles in limiting inflammatory responses upon TLR stimulation, for which we further studied their implication in the TLR5 alterations observed in AD. We validated the up-regulation of TLR5 in the frontal cortex of moderate AD cases. In addition, we observed up-regulation of the TAM ligands protein S (PROS1), galectin-3 (LGALS3), and Tulp-1. Furthermore, we identified an association of the TAM ligand GAS6 with AD progression. In THP-1 cells, co-stimulation with Aβ and flagellin for 24 h induced up-regulation of TYRO3 and GAS6, which could be prevented by neutralization of TLR5. Our results underscore the role of TLR dysregulations in AD, suggesting the presence of an immunosuppressive response during moderate disease stages, and implicate TAM signaling in AD immune dysregulation.
Disciplines :
Neurology
Author, co-author :
Herrera-Rivero, Marisol; Department of Neurodegenerative Disease and Gerontopsychiatry / Neurology, University of Bonn Medical Center, Sigmund-Freud-Str. 25, 53127, Bonn, Germany ; Department of Genomics, Life & Brain Research Center and Institute of Human Genetics, University of Bonn Medical School and University Hospital Bonn, Bonn, Germany
Santarelli, Francesco; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Brosseron, Frederic; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Kummer, Markus P; Department of Neurodegenerative Disease and Gerontopsychiatry / Neurology, University of Bonn Medical Center, Sigmund-Freud-Str. 25, 53127, Bonn, Germany
HENEKA, Michael ; Department of Neurodegenerative Disease and Gerontopsychiatry / Neurology, University of Bonn Medical Center, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. michael.heneka@ukbonn.de ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. michael.heneka@ukbonn.de
External co-authors :
yes
Language :
English
Title :
Dysregulation of TLR5 and TAM Ligands in the Alzheimer's Brain as Contributors to Disease Progression.
Funding Information Financial support for this study was obtained through the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AETIONOMY (grant #115568) and the INMiND Project of the European Union to MTH.
Castello MA, Soriano S (2014) On the origin of Alzheimer’s disease. Trials and tribulations of the amyloid hypothesis. Ageing Res Rev 13:10–12
Bardou I, Kaercher RM, Brothers HM, Hopp SC, Royer S, Wenk GL (2014) Age and duration of inflammatory environment differentially affect the neuroimmune response and catecholaminergic neurons in the midbrain and brainstem. Neurobiol Aging 35(5):1065–1073
Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O (2013) Neuroinflammation and psychiatric illness. J Neuroinflammation 10:43
Heneka MT, Kummer MP, Latz E (2014) Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14(7):463–477
Sastre M, Klockgether T, Heneka MT (2006) Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms. Int J Dev Neurosci 24(2–3):167–176
Doens D, Fernández PL (2014) Microglia receptors and their implications in the response to amyloid β for Alzheimer’s disease pathogenesis. J Neuroinflammation 11:48
Heneka MT, Golenbock DT, Latz E (2015) Innate immunity in Alzheimer’s disease. Nat Immunol 16(3):229–236
Chouraki V, Seshadri S (2014) Genetics of Alzheimer’s disease. Adv Genet 87:245–294
Gale SC, Gao L, Mikacenic C, Coyle SM, Rafaels N, Murray Dudenkov T, Madenspacher JH, Draper DW et al (2014) APOε4 is associated with enhanced in vivo innate immune responses in human subjects. J Allergy Clin Immunol 134(1):127–134
Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45(12):1452–1458
International Genomics of Alzheimer’s Disease Consortium (IGAP) (2015) Convergent genetic and expression data implicate immunity in Alzheimer’s disease. Alzheimers Dement 11(6):658–671
Trudler D, Farfara D, Frenkel D (2010) Toll-like receptors expression and signaling in glia cells in neuro-amyloidogenic diseases: towards future therapeutic application. Mediators Inflamm 2010:497987. 10.1155/2010/497987
Hanisch UK, Johnson TV, Kipnis J (2008) Toll-like receptors: roles in neuroprotection? Trends Neurosci 31(4):176–182
Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G (2007) TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131(6):1124–1136
Lemke G (2013) Biology of the TAM receptors. Cold Spring Harb Perspect Biol 5(11):a009076
Linger RM, Keating AK, Earp HS, Graham DK (2008) TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res 100:35–83
Brown JE, Krodel M, Pazos M, Lai C, Prieto AL (2012) Cross-phosphorylation, signaling and proliferative functions of the Tyro3 and Axl receptors in Rat2 cells. PLoS One 7(5):e36800
Tsou WI, Nguyen KQ, Calarese DA, Garforth SJ, Antes AL, Smirnov SV et al (2014) Receptor tyrosine kinases, TYRO3, AXL and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation. J Biol Chem 289(37):25750–25763
Pierce AM, Keating AK (2014) TAM receptor tyrosine kinases: expression, disease and oncogenesis in the central nervous system. Brain Res 1542:206–220
Zheng Y, Wang Q, Xiao B, Lu Q, Wang Y, Wang X (2012) Involvement of receptor tyrosine kinase Tyro3 in amyloidogenic APP processing and β-amyloid deposition in Alzheimer’s disease models. PLoS One 7(6):e39035
Li Q, Lu Q, Lu H, Tian S, Lu Q (2013) Systemic autoimmunity in TAM triple knockout mice causes inflammatory brain damage and cell death. PLoS One 8(6):e64812
Ji R, Tian S, Lu HJ, Lu Q, Zheng Y, Wang X, Ding J, Li Q et al (2013) TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation. J Immunol 191(12):6165–6177
Voyle N, Keohane A, Newhouse S, Lunnon K, Johnston C, Soininen H, Kloszewska I, Mecocci P et al (2016) A pathway based classification method for analyzing gene expression for Alzheimer’s disease diagnosis. J Alzheimers Dis 49(3):659–669
Waterhouse AM, Procter JB, Martin DM, Clamp M, Barton GJ (2009) Jalview version 2—a multiple sequence alignment editor and analysis workbench. Bioinformatics 25(9):1189–1191
Tovchigrechko A, Vakser IA (2006) GRAMM-X public web server for protein-protein docking. Nucleic Acids Res 34(Web Server issue:W310–W314)
Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18(15):2714–2723
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28(1):235–242. www.rcsb.org
Arroyo DS, Soria JA, Gaviglio EA, Rodriguez-Galan MC, Iribarren P (2011) Toll-like receptors are key players in neurodegeneration. Int Immunopharmacol 11(10):1415–1421
Frank S, Copanaki E, Burbach GJ, Müller UC, Deller T (2009) Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice. Neurosci Lett 453(1):41–44
Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K (2006) Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 129(Pt 11:3006–3019)
Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi K (2008) Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 5:23
Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A, Siler DA, Markesbery WR et al (2008) Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol 213(1):114–121
Landreth GE, Reed-Geaghan EG (2009) Toll-like receptors in Alzheimer’s disease. Curr Top Microbiol Immunol 336:137–153
Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, Rube CE, Walter J et al (2012) TLR2 is a primary receptor for Alzheimer’s amyloid β peptide to trigger neuroinflammatory activation. J Immunol 188(3):1098–1107
Honjo K, van Reekum R, Verhoeff NP (2009) Alzheimer’s disease and infection: do infectious agents contribute to progression of Alzheimer’s disease? Alzheimers Dement 5(4):348–360
Miklossy J (2011) Alzheimer’s disease—a neurospirochetosis. Analysis of the evidence following Koch’s and Hill’s criteria. J Neuroinflammation 8:90
Maheshwari P, Eslick GD (2015) Bacterial infection and Alzheimer’s disease: a meta-analysis. J Alzheimers Dis 43(3):957–966
Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R et al (2010) Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328(5975):228–231
Letiembre M, Liu Y, Walter S, Hao W, Pfander T, Wrede A, Schulz-Schaeffer W, Fassbender K (2009) Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. Neurobiol Aging 30(5):759–768
Downer EJ (2013) Toll-like receptor signaling in Alzheimer’s disease progression. J Alzheimers Dis Parkinsonism S10:006. 10.4172/2161-0460.S10-006
Chakrabarty P, Li A, Ladd TB, Strickland MR, Koller EJ, Burgess JD, Funk CC, Cruz PE et al (2018) TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease. J Exp Med 215(9):2247–2264
Lim SL, Rodriguez-Ortiz CJ, Kitazawa M (2015) Infection, systemic inflammation, and Alzheimer’s disease. Microbes Infect 17(8):549–556
Herrera-Rivero M, Heneka MT (2016) Expression of the TAM system in frontal cortex of Alzheimer’s disease in early stages. (Conference) Degeneration and Regeneration in Musculoskeletal and Neurodegenerative Diseases. Trelleborg, Sweden. 10.13140/RG.2.1.1826.8561
Mattsson N, Insel P, Nosheny R, Zetterberg H, Trojanowski JQ, Shaw LM et al (2013) CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders. Transl Psychiatry 3:e293
Kiddle SJ, Thambisetty M, Simmons A, Riddoch-Contreras J, Hye A, Westman E, Pike I, Ward M et al (2012) Plasma based markers of [11C] PiB-PET brain amyloid burden. PLoS One 7(9):e44260
Sainaghi PP, Bellan M, Lombino F, Alciato F, Carecchio M, Galimberti D, Fenoglio C, Scarpini E et al (2017) Growth arrest specific 6 concentration is increased in the cerebrospinal fluid of patients with Alzheimer’s disease. J Alzheimers Dis 55(1):59–65
