Innate immunity stimulation via toll-like receptor 9 ameliorates vascular amyloid pathology in Tg-SwDI mice with associated cognitive benefits

Journal of Neuroscience

Volumn 37, Issue 4, 2017, Pages 936-959

  Scholtzova, Henrieta ^a   Do, Eileen ^a   Dhakal, Shleshma ^a   Sun, Yanjie ^a   Liu, Shan ^a   Mehta, Pankaj D ^b   Wisniewski, Thomas ^a  

^a NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b NEW YORK STATE INSTITUTE FOR BASIC RESEARCH IN DEVELOPMENTAL DISABILITIES   (United States)

Author keywords

Alzheimer s disease; Amyloid ; Immunomodulation; Innate immunity; Toll like receptor 9; Transgenic mice

Indexed keywords

AMYLOID; CYTOKINE; OLIGODEOXYNUCLEOTIDE; TOLL LIKE RECEPTOR 9; CPG ODN 1826; OLIGODEOXYRIBONUCLEOTIDE; TLR9 PROTEIN, MOUSE; AMYLOID BETA PROTEIN; CPG OLIGODEOXYNUCLEOTIDE;

ALZHEIMER DISEASE; ANIMAL EXPERIMENT; ARTICLE; ASTROCYTOSIS; BEHAVIOR; COGNITION; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; IMMUNE RESPONSE; IMMUNOCOMPETENT CELL; IMMUNOHISTOCHEMISTRY; IMMUNOREACTIVITY; IMMUNOTHERAPY; INNATE IMMUNITY; MALE; MICROGLIA; MOUSE; NEUROFIBRILLARY TANGLE; NONHUMAN; NOVEL OBJECT RECOGNITION TEST; PRIORITY JOURNAL; VASCULAR AMYLOIDOSIS; AGONISTS; ANIMAL; C57BL MOUSE; CEREBRAL AMYLOID ANGIOPATHY; DRUG EFFECTS; HUMAN; IMMUNOLOGY; METABOLISM; PHYSIOLOGY; PLAQUE, AMYLOID; TRANSGENIC MOUSE; ADVERSE DRUG REACTION; ANIMAL CELL; ANIMAL MODEL; ANIMAL TISSUE; BRAIN TISSUE; COGNITIVE DEFECT; COHORT ANALYSIS; CONTROLLED STUDY; DISEASE ASSOCIATION; DRUG MECHANISM; DRUG SAFETY; FUNCTIONAL ASSESSMENT; IMMUNOMODULATION; IMMUNOSTIMULATION; MEMORY DISORDER; MOUSE STRAIN; RADIAL ARM MAZE TEST; RECOGNITION; SHORT TERM MEMORY; SPATIAL MEMORY; TAUOPATHY; TG-SWDI MOUSE; WORKING MEMORY;

ANIMALS; CEREBRAL AMYLOID ANGIOPATHY; COGNITION; FEMALE; HUMANS; IMMUNITY, INNATE; MALE; MICE; MICE, INBRED C57BL; MICE, TRANSGENIC; OLIGODEOXYRIBONUCLEOTIDES; PLAQUE, AMYLOID; TOLL-LIKE RECEPTOR 9;

EID: 85010910678     PISSN: 02706474     EISSN: 15292401     Source Type: Journal    
DOI: 10.1523/JNEUROSCI.1967-16.2016     Document Type: Article

References (77)

1. Asuni AA, Boutajangout A, Scholtzova H, Knudsen E, Li YS, Quartermain D, Frangione B, Wisniewski T, Sigurdsson EM (2006) Vaccination of Alzheimer’s model mice with Abeta derivative in alum adjuvant reduces Abeta burden without microhemorrhages. Eur J Neurosci 24:2530–2542.
2. Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM (2007) Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci 27:9115–9129.
3. Boutajangout A, Quartermain D, Sigurdsson EM (2010) Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci 30:16559–16566.
4. Boutajangout A, Li YS, Quartermain D, Sigurdsson EM (2012) Cognitive and sensorimotor tasks for assessing functional impairments in mouse models of Alzheimer’s disease and related disorders. Methods Mol Biol 849:529–540.
5. Brothers HM, Wilcock DM (2013) Are inflammatory profiles the key to personalized Alzheimer’s treatment? Neurodegener Dis Manag 3:343-351.
6. Campbell JD, Cho Y, Foster ML, Kanzler H, Kachura MA, Lum JA, Ratcliffe MJ, Sathe A, Leishman AJ, Bahl A, McHale M, Coffman RL, Hessel EM (2009) CpG-containing immunostimulatory DNA sequences elicit TNFalpha-dependent toxicity in rodents but not in humans. J Clin Invest 119:2564–2576.
7. Cao T, Thomas TC, Ziebell JM, Pauly JR, Lifshitz J (2012) Morphological and genetic activation of microglia after diffuse traumatic brain injury in the rat. Neuroscience 225:65–75.
8. Celhar T, Pereira-Lopes S, Thornhill SI, Lee HY, Dhillon MK, Poidinger M, Connolly JE, Lim LH, Biswas SK, Fairhurst AM (2016) TLR7 and TLR9 ligands regulate antigen presentation by macrophages. Int Immunol 28: 223–232.
9. Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB, Morris RG (2000) A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer’s disease. Nature 408:975–979.
10. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25:9275–9284.
11. Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, Van Nostrand WE (2004) Early-onset and robust cerebral microvascular ac cumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid betaprotein precursor. J Biol Chem 279:20296–20306.
12. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM (2002) Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci 5:452–457.
13. Doi Y, Mizuno T, Maki Y, Jin S, Mizoguchi H, Ikeyama M, Doi M, Michikawa M, Takeuchi H, Suzumura A (2009) Microglia activated with the tolllike receptor 9 ligand CpG attenuate oligomeric amyloid {beta} neurotoxicity in in vitro and in vivo models of Alzheimer’s disease. Am J Pathol 175:2121–2132.
14. Durafourt BA, Moore CS, Zammit DA, Johnson TA, Zaguia F, Guiot MC, Bar-Or A, Antel JP (2012) Comparison of polarization properties of human adult microglia and blood-derived macrophages. Glia 60:717–727.
15. ElAli A, Rivest S (2016) Microglia in Alzheimer’s disease: a multifaceted relationship. Brain Behav Immun 55:138–150.
16. Feng Y, Li L, Sun XH (2011) Monocytes and Alzheimer’s disease. Neurosci Bull 27:115–122.
17. Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, Cheung TH, Zhang B, Fu WY, Liew FY, Ip NY (2016) IL-33 ameliorates Alzheimer’s diseaselike pathology and cognitive decline. Proc Natl Acad Sci U S A 113: E2705–E2713.
18. Galea I, Palin K, Newman TA, Van Rooijen N, Perry VH, Boche D (2005) Mannose receptor expression specifically reveals perivascular macrophages in normal, injured, and diseased mouse brain. Glia 49:375–384.
19. Goñi F, Herline K, Peyser D, Wong K, Ji Y, Sun Y, Mehta P, Wisniewski T (2013) Immunomodulation targeting of both Abeta and tau pathological conformers ameliorates Alzheimer’s disease pathology in TgSwDI and 3xTg mouse models. J Neuroinflammation 10:150.
20. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35.
21. Guerrero AR, Uchida K, Nakajima H, Watanabe S, Nakamura M, Johnson WE, Baba H (2012) Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice. J Neuroinflammation 9:40.
22. Guillemin GJ, Brew BJ (2004) Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol 75:388–397.
23. Guillot-Sestier MV, Doty KR, Gate D, Rodriguez J Jr, Leung BP, Rezai-Zadeh K, Town T (2015a) Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 85:534–548.
24. Guillot-Sestier MV, Doty KR, Town T (2015b) Innate immunity fights Alzheimer’s disease. Trends Neurosci 38:674–681.
25. Hanke ML, Kielian T (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond) 121:367-387.
26. Hawkes CA, McLaurin J (2009) Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc Natl Acad Sci U S A 106:1261–1266.
27. He H, Xu J, Warren CM, Duan D, Li X, Wu L, Iruela-Arispe ML (2012) Endothelial cells provide an instructive niche for the differentiation and functional polarization of M2-like macrophages. Blood 120:3152–3162.
28. Heikenwalder M, Polymenidou M, Junt T, Sigurdson C, Wagner H, Akira S, Zinkernagel R, Aguzzi A (2004) Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med 10:187–192.
29. Heneka M, Andreasson KI, Bachstetter AD, Colonna M, Ginhoux F, Holmes C, Lamb B, Landreth G, Lee DC, Low D, Lynch MA, Monsonego A, O’Banion MK, Pekny M, Puschmann T, Russek-Blum N, Sandusky LA, Selenica ML, Takata K, Teeling J, Town T, Van Eldik LJ. and Schulz JB (2016) Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem 138:653–693.
30. Iliev AI, Stringaris AK, Nau R, Neumann H (2004) Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9). FASEB J 18:412–414.
31. Iribarren P, Chen K, Hu J, Gong W, Cho EH, Lockett S, Uranchimeg B, Wang JM (2005) 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 19:2032–2034.
32. Jaeger LB, Dohgu S, Sultana R, Lynch JL, Owen JB, Erickson MA, Shah GN, Price TO, Fleegal-Demotta MA, Butterfield DA, Banks WA (2009) Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer’s disease. Brain, Behav Immun 23:507–517.
33. Jucker M, Heppner FL (2008) Cerebral and peripheral amyloid phagocytes—an old liaison with a new twist. Neuron 59:8–10.
34. Karch CM, Cruchaga C, Goate AM (2014) Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83:11–26.
35. Kitazawa M, Cheng D, Tsukamoto MR, Koike MA, Wes PD, Vasilevko V, Cribbs DH, LaFerla FM (2011) Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal beta-catenin pathway function in an Alzheimer’s disease model. J Immunol 187:6539-6549.
36. Krieg AM (2002) From A to Z on CpG. Trends Immunol 23:64–65.
37. Krieg AM (2012) CpG still rocks! Update on an accidental drug. Nucleic Acid Ther 22:77–89.
38. Lai AY, McLaurin J (2012) Clearance of amyloid-beta peptides by microglia and macrophages: the issue of what, when and where. Future Neurol 7:165–176.
39. Lampron A, Elali A, Rivest S (2013a) Innate immunity in the CNS: redefining the relationship between the CNS and its environment. Neuron 78: 214–232.
40. Lampron A, Pimentel-Coelho PM, Rivest S (2013b) Migration of bone marrow-derived cells into the central nervous system in models of neurodegeneration. J Comp Neurol 521:3863–3876.
41. Latta CH, Brothers HM, Wilcock DM (2015) Neuroinflammation in Alzheimer’s disease; a source of heterogeneity and target for personalized therapy. Neuroscience 302:103–111.
42. Lee DC, Rizer J, Hunt JB, Selenica ML, Gordon MN, Morgan D (2013) Review: experimental manipulations of microglia in mouse models of Alzheimer’s pathology: activation reduces amyloid but hastens tau pathology. Neuropathol Appl Neurobiol 39:69–85.
43. Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, Hong JT (2008) Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation 5:37.
44. Lesné SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, Ashe KH (2013) Brain amyloid-beta oligomers in ageing and Alzheimer’s disease. Brain 136:1383–1398.
45. Liu S, Breitbart A, Sun Y, Mehta PD, Boutajangout A, Scholtzova H, Wisniewski T (2014) Blocking the apolipoprotein E/amyloid beta interaction in triple transgenic mice ameliorates Alzheimer’s disease related amyloid beta and tau pathology. J Neurochem 128:577–591.
46. Miao J, Xu F, Davis J, Otte-Höller I, Verbeek MM, Van Nostrand WE (2005) 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 167:505–515.
47. Michaud JP, Rivest S (2015) Anti-inflammatory signaling in microglia exacerbates Alzheimer’s disease-related pathology. Neuron 85:450–452.
48. Michaud JP, Hallé M, Lampron A, Thériault P, Préfontaine P, Filali M, Tribout-Jover P, Lanteigne AM, Jodoin R, Cluff C, Brichard V, Palmantier R, Pilorget A, Larocque D, Rivest S (2013) Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology. Proc Natl Acad Sci U S A 110: 1941–1946.
49. Minett T, Classey J, Matthews FE, Fahrenhold M, Taga M, Brayne C, Ince PG, Nicoll JA, Boche D, Boche D (2016) Microglial immunophenotype in dementia with Alzheimer’s pathology. J Neuroinflammation 13:135.
50. Morgan D, Gordon MN, Tan J, Wilcock D, Rojiani AM (2005) Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics. J Neuropathol Exp Neurol 64:743–753.
51. Mrak RE, Griffin WS (2001) Interleukin-1, neuroinflammation, and Alzheimer’s disease. Neurobiol Aging 22:903–908.
52. Piazza F, Winblad B (2016) Amyloid-related imaging abnormalities (ARIA) in immunotherapy trials for Alzheimer’s disease: need for prognostic biomarkers? J Alzheimers Dis 52:417–420.
53. Prokop S, Miller KR, Drost N, Handrick S, Mathur V, Luo J, Wegner A, Wyss-Coray T, Heppner FL (2015) Impact of peripheral myeloid cells on amyloid-beta pathology in Alzheimer’s disease-like mice. J Exp Med 212:1811–1818.
54. Rego Â, Viana SD, Ribeiro CA, Rodrigues-Santos P, Pereira FC (2016) Monophosphoryl lipid-A: a promising tool for Alzheimer’s disease toll. J Alzheimers Dis 52:1189–1202.
55. Richard KL, Filali M, Préfontaine P, Rivest S (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.
56. Sakai K, Boche D, Carare R, Johnston D, Holmes C, Love S, Nicoll JA (2014) Abeta immunotherapy for Alzheimer’s disease: effects on apoE and cerebral vasculopathy. Acta Neuropathol 128:777–789.
57. Schellenberg GD, Montine TJ (2012) The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathol 124:305–323.
58. Schmidt SD, Nixon RA, Mathews PM (2005) ELISA method for measurement of amyloid-beta levels. Methods Mol Biol 299:279–297.
59. Scholtzova H, Wadghiri YZ, Douadi M, Sigurdsson EM, Li YS, Quartermain D, Banerjee P, Wisniewski T (2008) Memantine leads to behavioral improvement and amyloid reduction in Alzheimer’s-disease-model transgenic mice shown as by micromagnetic resonance imaging. J Neurosci Res 86:2784–2791.
60. Scholtzova H, Kascsak RJ, Bates KA, Boutajangout A, Kerr DJ, Meeker HC, Mehta PD, Spinner DS, Wisniewski T (2009) Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer’s diseaserelated pathology. J Neurosci 29:1846–1854.
61. Scholtzova H, Chianchiano P, Pan J, Sun Y, Goñi F, Mehta PD, Wisniewski T (2014) Amyloid β and Tau Alzheimer’s disease related pathology is reduced by Toll-like receptor 9 stimulation. Acta Neuropathol Commun 2:101.
62. Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M (2012) Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol 11:241–249.
63. Streit WJ, Braak H, Xue QS, Bechmann I (2009) Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 118:475–485.
64. Streit WJ, Xue QS, Tischer J, Bechmann I (2014) Microglial pathology. Acta Neuropathol Commun 2:142.
65. Su F, Bai F, Zhou H, Zhang Z (2016) Reprint of: Microglial toll-like receptors and Alzheimer’s disease. Brain Behav Immun 55:166–178.
66. 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: 3006–3019.
67. Van Vickle GD, Esh CL, Daugs ID, Kokjohn TA, Kalback WM, Patton RL, Luehrs DC, Walker DG, Lue LF, Beach TG, Davis J, Van Nostrand WE, Castaño EM, Roher AE (2008) Tg-SwDI transgenic mice exhibit novel alterations in AbetaPP processing, Abeta degradation, and resilient amyloid angiopathy. Am J Pathol 173:483–493.
68. Vidoni ED, Yeh HW, Morris JK, Newell KL, Alqahtani A, Burns NC, Burns JM, Billinger SA (2016) Cerebral beta-amyloid angiopathy is associated with earlier dementia onset in Alzheimer’s disease. Neurodegener Dis 16:218–224.
69. Vollmer J, Krieg AM (2009) Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists. Adv Drug Deliv Rev 61:195–204.
70. Wes PD, Sayed FA, Bard F, Gan L (2016) Targeting microglia for the treatment of Alzheimer’s Disease. Glia 64:1710–1732.
71. Wilcock DM, Colton CA (2009) Immunotherapy, vascular pathology, and microhemorrhages in transgenic mice. CNS Neurol Disord Drug Targets 8:50–64.
72. Wisniewski T, Drummond E (2016) Developing therapeutic vaccines against Alzheimer’s disease. Expert Rev Vaccines 15:401–415.
73. Wisniewski T, Goñi F (2015) Immunotherapeutic approaches for Alzheimer’s disease. Neuron 85:1162–1176.
74. Yamada M (2015) Cerebral amyloid angiopathy: emerging concepts. J Stroke 17:17–30.
75. Yang J, Ji Y, Mehta P, Bates KA, Sun Y, Wisniewski T (2011) Blocking the apolipoprotein E/amyloid-beta interaction reduces fibrillar vascular amyloid deposition and cerebral microhemorrhages in TgSwDI mice. J Alzheimers Dis 24:269–285.
76. Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquist S, Narayanan M, Suver C, Shah H, Mahajan M, Gillis T, Mysore J, MacDonald ME et al. (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153:707–720.
77. Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S, Neal JW, Love S, Nicoll JA, Boche D (2013) Inflammatory components in human Alzheimer’s disease and after active amyloid-beta42 immunization. Brain 136:2677–2696.