Soluble amyloid triggers a myeloid differentiation factor 88 and interferon regulatory factor 7 dependent neuronal type-1 interferon response in vitro

Journal of Neuroinflammation

Volumn 12, Issue 1, 2015, Pages

  Minter, Myles Robert ^a   Main, Bevan Scott ^a   Brody, Kate Maree ^a   Zhang, Moses ^a   Taylor, Juliet Marie ^a   Crack, Peter John ^a  

^a UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

Alzheimer's disease; Amyloid; Cytokines; IRF7; JAK STAT; Myd88; Neuro inflammation; Toll like receptor; Type 1 interferon

Indexed keywords

ALPHA INTERFERON; AMYLOID BETA PROTEIN[1-42]; BETA INTERFERON; INTERFERON; INTERFERON REGULATORY FACTOR 7; INTERLEUKIN 1BETA; INTERLEUKIN 6; LIPOPOLYSACCHARIDE; MESSENGER RNA; MYELOID DIFFERENTIATION FACTOR 88; SHORT HAIRPIN RNA; STAT3 PROTEIN; TUMOR NECROSIS FACTOR ALPHA; AMYLOID BETA PROTEIN; AMYLOID BETA-PROTEIN (1-42); MYD88 PROTEIN, HUMAN; PEPTIDE FRAGMENT; SMALL INTERFERING RNA;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CELL VIABILITY; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOKINE RESPONSE; CYTOTOXICITY; EMBRYO; FEMALE; GENE EXPRESSION REGULATION; HUMAN; HUMAN CELL; IFN ALPHA GENE; IFN BETA GENE; IL 1BETA GENE; IL 6 GENE; IN VITRO STUDY; MOUSE; MTS ASSAY; NEUROBLASTOMA CELL; NEUROTOXICITY; NONHUMAN; PHARMACOLOGICAL BLOCKING; POLYMERASE CHAIN REACTION; PRIMARY CULTURE; PROTEIN DETERMINATION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; QUANTITATIVE ANALYSIS; SIGNAL TRANSDUCTION; STABLE EXPRESSION; TNF ALPHA GENE; WESTERN BLOTTING; ANALYSIS OF VARIANCE; ANIMAL; CELL CULTURE; DOSE RESPONSE; DRUG EFFECTS; GENETIC TRANSFECTION; GENETICS; MAMMALIAN EMBRYO; METABOLISM; NEUROBLASTOMA; PATHOLOGY; TRANSGENIC MOUSE;

AMYLOID BETA-PEPTIDES; ANALYSIS OF VARIANCE; ANIMALS; CELLS, CULTURED; DOSE-RESPONSE RELATIONSHIP, DRUG; EMBRYO, MAMMALIAN; GENE EXPRESSION REGULATION; HUMANS; INTERFERON REGULATORY FACTOR-7; INTERFERON TYPE I; LIPOPOLYSACCHARIDES; MICE; MICE, TRANSGENIC; MYELOID DIFFERENTIATION FACTOR 88; NEUROBLASTOMA; PEPTIDE FRAGMENTS; RNA, MESSENGER; RNA, SMALL INTERFERING; TRANSFECTION;

EID: 84949116166     PISSN: None     EISSN: 17422094     Source Type: Journal    
DOI: 10.1186/s12974-015-0263-2     Document Type: Article

References (100)

1. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986;83:4913-7.
2. Selkoe DJ. Alzheimer's disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis. 2001;3:75-80.
3. Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K. Role of toll-like receptor signalling in Abeta uptake and clearance. Brain. 2006;129:3006-19.
4. Apelt J, Schliebs R. Beta-amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology. Brain Res. 2001;894:21-30.
5. Salminen A, Ojala J, Suuronen T, Kaarniranta K, Kauppinen A. Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer's pathology. J Cell Mol Med. 2008;12:2255-62.
6. Blasko I, Marx F, Steiner E, Hartmann T, Grubeck-Loebenstein B. TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J. 1999;13:63-8.
7. Hanisch UK. Microglia as a source and target of cytokines. Glia. 2002;40:140-55.
8. Ye L, Huang Y, Zhao L, Li Y, Sun L, Zhou Y, et al. IL-1beta and TNF-alpha induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J Neurochem. 2013;125:897-908.
9. Floden AM, Combs CK. Beta-amyloid stimulates murine postnatal and adult microglia cultures in a unique manner. J Neurosci. 2006;26:4644-8.
10. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493:674-8.
11. Taylor JM, Minter MR, Newman AG, Zhang M, Adlard PA, Crack PJ. Type-1 interferon signaling mediates neuro-inflammatory events in models of Alzheimer's disease. Neurobiol Aging. 2014;35:1012-23.
12. Novikov A, Cardone M, Thompson R, Shenderov K, Kirschman KD, Mayer-Barber KD, et al. Mycobacterium tuberculosis triggers host type I IFN signaling to regulate IL-1beta production in human macrophages. J Immunol. 2011;187:2540-7.
13. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458:514-8.
14. Downes CE, Crack PJ. Neural injury following stroke: are toll-like receptors the link between the immune system and the CNS? Br J Pharmacol. 2010;160:1872-88.
15. Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci. 2008;1143:1-20.
16. Kawai T, Akira S. Signaling to NF-kappaB by toll-like receptors. Trends Mol Med. 2007;13:460-9.
17. Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. Biol Pharm Bull. 2005;28:886-92.
18. Mishra BB, Mishra PK, Teale JM. Expression and distribution of toll-like receptors in the brain during murine neurocysticercosis. J Neuroimmunol. 2006;181:46-56.
19. Salminen A, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Inflammation in Alzheimer's disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol. 2009;87:181-94.
20. Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, et al. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide. Brain. 2005;128:1778-89.
21. Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci. 2009;29:11982-92.
22. Lim JE, Kou J, Song M, Pattanayak A, Jin J, Lalonde R, et al. MyD88 deficiency ameliorates beta-amyloidosis in an animal model of Alzheimer's disease. Am J Pathol. 2011;179:1095-103.
23. Lim JE, Song M, Jin J, Kou J, Pattanayak A, Lalonde R, et al. The effects of MyD88 deficiency on exploratory activity, anxiety, motor coordination, and spatial learning in C57BL/6 and APPswe/PS1dE9 mice. Behav Brain Res. 2012;227:36-42.
24. Michaud JP, Richard KL, Rivest S. MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease. Mol Neurodegener. 2011;6:5.
25. Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi K. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease. J Neuroinflammation. 2008;5:23.
26. Song M, Jin J, Lim JE, Kou J, Pattanayak A, Rehman JA, et al. TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease. J Neuroinflammation. 2011;8:92.
27. de Weerd NA, Nguyen T. The interferons and their receptors - distribution and regulation. Immunol Cell Biol. 2012;90:483-91.
28. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1:135-45.
29. Barbalat R, Ewald SE, Mouchess ML, Barton GM. Nucleic acid recognition by the innate immune system. Annu Rev Immunol. 2011;29:185-214.
30. Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol. 2006;7:131-7.
31. de Weerd NA, Samarajiwa SA, Hertzog PJ. Type I interferon receptors: biochemistry and biological functions. J Biol Chem. 2007;282:20053-7.
32. Wan J, Fu AK, Ip FC, Ng HK, Hugon J, Page G, et al. Tyk2/STAT3 signaling mediates beta-amyloid-induced neuronal cell death: implications in Alzheimer's disease. J Neurosci. 2010;30:6873-81.
33. Honda K, Taniguchi T. IRFs: master regulators of signalling by toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol. 2006;6:644-58.
34. Yang H, Lin CH, Ma G, Baffi MO, Wathelet MG. Interferon regulatory factor-7 synergizes with other transcription factors through multiple interactions with p300/CBP coactivators. J Biol Chem. 2003;278:15495-504.
35. Lee MN, Ye C, Villani AC, Raj T, Li W, Eisenhaure TM, et al. Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science. 2014;343:1246980.
36. Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science. 2014;346:89-93.
37. Ning S, Pagano JS, Barber GN. IRF7: activation, regulation, modification and function. Genes Immun. 2011;12:399-414.
38. Kim TW, Staschke K, Bulek K, Yao J, Peters K, Oh KH, et al. A critical role for IRAK4 kinase activity in toll-like receptor-mediated innate immunity. J Exp Med. 2007;204:1025-36.
39. Koziczak-Holbro M, Joyce C, Gluck A, Kinzel B, Muller M, Tschopp C, et al. IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and toll-like receptor 7-mediated signaling and gene expression. J Biol Chem. 2007;282:13552-60.
40. Konno H, Yamamoto T, Yamazaki K, Gohda J, Akiyama T, Semba K, et al. TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNA. PLoS One. 2009;4, e5674.
41. Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol. 2004;5:1061-8.
42. Marie I, Durbin JE, Levy DE. Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7. EMBO J. 1998;17:6660-9.
43. Sato M, Hata N, Asagiri M, Nakaya T, Taniguchi T, Tanaka N. Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. FEBS Lett. 1998;441:106-10.
44. Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, Sakagami M, et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity. 1998;9:143-50.
45. Downes CE, Wong CH, Henley KJ, Guio-Aguilar PL, Zhang M, Ates R, et al. MyD88 is a critical regulator of hematopoietic cell-mediated neuroprotection seen after stroke. PLoS One. 2013;8, e57948.
46. Barnham KJ, Ciccotosto GD, Tickler AK, Ali FE, Smith DG, Williamson NA, et al. Neurotoxic, redox-competent Alzheimer's beta-amyloid is released from lipid membrane by methionine oxidation. J Biol Chem. 2003;278:42959-65.
47. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, et al. Cu(II) potentiation of Alzheimer Abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem. 1999;274:37111-6.
48. Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, et al. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron. 2008;59:43-55.
49. Varadarajan S, Kanski J, Aksenova M, Lauderback C, Butterfield DA. Different mechanisms of oxidative stress and neurotoxicity for Alzheimer's A beta(1-42) and A beta(25-35). J Am Chem Soc. 2001;123:5625-31.
50. Hung LW, Ciccotosto GD, Giannakis E, Tew DJ, Perez K, Masters CL, et al. Amyloid-beta peptide (Abeta) neurotoxicity is modulated by the rate of peptide aggregation: Abeta dimers and trimers correlate with neurotoxicity. J Neurosci. 2008;28:11950-8.
51. Smith JP, Lal V, Bowser D, Cappai R, Masters CL, Ciccotosto GD. Stimulus pattern dependence of the Alzheimer's disease amyloid-beta 42 peptide's inhibition of long term potentiation in mouse hippocampal slices. Brain Res. 2009;1269:176-84.
52. Ciccotosto GD, Tew D, Curtain CC, Smith D, Carrington D, Masters CL, et al. Enhanced toxicity and cellular binding of a modified amyloid beta peptide with a methionine to valine substitution. J Biol Chem. 2004;279:42528-34.
53. Schmid AW, Freir DB, Herron CE. Inhibition of LTP in vivo by beta-amyloid peptide in different conformational states. Brain Res. 2008;1197:135-42.
54. Smith DP, Ciccotosto GD, Tew DJ, Fodero-Tavoletti MT, Johanssen T, Masters CL, et al. Concentration dependent Cu2+ induced aggregation and dityrosine formation of the Alzheimer's disease amyloid-beta peptide. Biochemistry. 2007;46:2881-91.
55. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402-8.
56. Buttke TM, McCubrey JA, Owen TC. Use of an aqueous soluble tetrazolium/formazan assay to measure viability and proliferation of lymphokine-dependent cell lines. J Immunol Methods. 1993;157:233-40.
57. Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, et al. TLR2 is a primary receptor for Alzheimer's amyloid beta peptide to trigger neuroinflammatory activation. J Immunol. 2012;188:1098-107.
58. Gao M, London N, Cheng K, Tamura R, Jin J, Schueler-Furman O, et al. Rationally designed macrocyclic peptides as synergistic agonists of LPS-induced inflammatory response. Tetrahedron. 2014;70:7664-8.
59. Oda M, Yamamoto H, Shibutani M, Nakano M, Yabiku K, Tarui T, et al. Vizantin inhibits endotoxin-mediated immune responses via the TLR 4/MD-2 complex. J Immunol. 2014;193:4507-14.
60. Zhang YY, Fan YC, Wang M, Wang D, Li XH. Atorvastatin attenuates the production of IL-1beta, IL-6, and TNF-alpha in the hippocampus of an amyloid beta1-42-induced rat model of Alzheimer's disease. Clin Interv Aging. 2013;8:103-10.
61. Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005;434:772-7.
62. Terry RD. The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis. J Neuropathol Exp Neurol. 1996;55:1023-5.
63. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999;46:860-6.
64. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol. 1999;155:853-62.
65. Brun A, Englund E. Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading. Histopathology. 1981;5:549-64.
66. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982;215:1237-9.
67. Owens T, Khorooshi R, Wlodarczyk A, Asgari N. Interferons in the central nervous system: a few instruments play many tunes. Glia. 2014;62:339-55.
68. Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A, et al. Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol. 2008;213:114-21.
69. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, et al. CD36 ligands promote sterile inflammation through assembly of a toll-like receptor 4 and 6 heterodimer. Nat Immunol. 2010;11:155-61.
70. Goll Y, Bekenstein U, Barbash S, Greenberg DS, Zangen R, Shoham S, et al. Sustained Alzheimer's amyloid pathology in myeloid differentiation protein-88-deficient APPswe/PS1 mice. Neuro-degenerative Diseases. 2014;13:58-60.
71. Hwang SY, Hur KY, Kim JR, Cho KH, Kim SH, Yoo JY. Biphasic RLR-IFN-beta response controls the balance between antiviral immunity and cell damage. J Immunol. 2013;190:1192-200.
72. Meylan E, Tschopp J. Toll-like receptors and RNA helicases: two parallel ways to trigger antiviral responses. Mol Cell. 2006;22:561-9.
73. Schneider K, Loewendorf A, De Trez C, Fulton J, Rhode A, Shumway H, et al. Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe. 2008;3:67-76.
74. Erta M, Quintana A, Hidalgo J. Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci. 2012;8:1254-66.
75. Frankola KA, Greig NH, Luo W, Tweedie D. Targeting TNF-alpha to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS & Neurol Disord Drug Targets. 2011;10:391-403.
76. Shaftel SS, Griffin WS, O'Banion MK. The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation. 2008;5:7.
77. Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT. Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci. 2014;8:315.
78. Rathinam VA, Vanaja SK, Waggoner L, Sokolovska A, Becker C, Stuart LM, et al. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell. 2012;150:606-19.
79. Lood C, Gullstrand B, Truedsson L, Olin AI, Alm GV, Ronnblom L, et al. C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. Arthritis Rheum. 2009;60:3081-90.
80. Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E, et al. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med. 2003;198:1043-55.
81. Ogasawara N, Sasaki M, Itoh Y, Tokudome K, Kondo Y, Ito Y, et al. Rebamipide suppresses TLR-TBK1 signaling pathway resulting in regulating IRF3/7 and IFN-alpha/beta reduction. J Clin Biochem Nutr. 2011;48:154-60.
82. Richez C, Yasuda K, Watkins AA, Akira S, Lafyatis R, van Seventer JM, et al. TLR4 ligands induce IFN-alpha production by mouse conventional dendritic cells and human monocytes after IFN-beta priming. J Immunol. 2009;182:820-8.
83. Rajbhandari L, Tegenge MA, Shrestha S, Ganesh Kumar N, Malik A, Mithal A, et al. Toll-like receptor 4 deficiency impairs microglial phagocytosis of degenerating axons. Glia. 2014;62:1982-91.
84. Sakaguchi S, Negishi H, Asagiri M, Nakajima C, Mizutani T, Takaoka A, et al. Essential role of IRF-3 in lipopolysaccharide-induced interferon-beta gene expression and endotoxin shock. Biochem Biophys Res Commun. 2003;306:860-6.
85. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol. 2003;4:491-6.
86. Sharma S. tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J. Triggering the interferon antiviral response through an IKK-related pathway. Science. 2003;300:1148-51.
87. Kaltschmidt B, Uherek M, Wellmann H, Volk B, Kaltschmidt C. Inhibition of NF-kappaB potentiates amyloid beta-mediated neuronal apoptosis. Proc Natl Acad Sci U S A. 1999;96:9409-14.
88. Terai K, Matsuo A, McGeer PL. Enhancement of immunoreactivity for NF-kappa B in the hippocampal formation and cerebral cortex of Alzheimer's disease. Brain Res. 1996;735:159-68.
89. Moynagh PN. TLR signalling and activation of IRFs: revisiting old friends from the NF-kappaB pathway. Trends Immunol. 2005;26:469-76.
90. Acarin L, Gonzalez B, Castellano B. Neuronal, astroglial and microglial cytokine expression after an excitotoxic lesion in the immature rat brain. Eur J Neurosci. 2000;12:3505-20.
91. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458-62.
92. Tracey KJ. The inflammatory reflex. Nature. 2002;420:853-9.
93. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384-8.
94. Rosas-Ballina M, Goldstein RS, Gallowitsch-Puerta M, Yang L, Valdes-Ferrer SI, Patel NB, et al. The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE. Mol Med. 2009;15:195-202.
95. Andersson U, Tracey KJ. Reflex principles of immunological homeostasis. Annu Rev Immunol. 2012;30:313-35.
96. Lombardo S, Maskos U. Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment. Neuropharmacology. 2014;doi:10.1016/j.neuropharm.2014.11.018 [Epub].
97. Kolisnyk B, Al-Onaizi MA, Hirata PH, Guzman MS, Nikolova S, Barbash S, et al. Forebrain deletion of the vesicular acetylcholine transporter results in deficits in executive function, metabolic, and RNA splicing abnormalities in the prefrontal cortex. J Neurosci Off J Soc Neurosci. 2013;33:14908-20.
98. Shaltiel G, Hanan M, Wolf Y, Barbash S, Kovalev E, Shoham S, et al. Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target. Brain Struct Funct. 2013;218:59-72.
99. Lau P, Bossers K, Janky R, Salta E, Frigerio CS, Barbash S, et al. Alteration of the microRNA network during the progression of Alzheimer's disease. EMBO Mol Med. 2013;5:1613-34.
100. Zimmerman G, Shaltiel G, Barbash S, Cohen J, Gasho CJ, Shenhar-Tsarfaty S, et al. Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFkappaB pathway. Transl Psychiatry. 2012;2, e78.