Targeting tumor necrosis factor alpha for Alzheimer’s disease

Current Alzheimer Research

Volumn 14, Issue 4, 2017, Pages 412-425

  Decourt, Boris ^a,b   Lahiri, Debomoy K ^c   Sabbagh, Marwan N ^d  

^a ARIZONA STATE UNIVERSITY   (United States)

^b SUN HEALTH RESEARCH INSTITUTE   (United States)

^c INDIANA UNIVERSITY   (United States)

^d BARROW NEUROLOGICAL INSTITUTE   (United States)

Author keywords

Alzheimer s disease; BACE1; Etanercept; Inflammation; Neuroinflammation; Thalidomide; TNF

Indexed keywords

CELASTROL; CHOLINESTERASE INHIBITOR; CORTICOSTEROID; ETANERCEPT; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 6; MINOCYCLINE; NICOTINE; NONSTEROID ANTIINFLAMMATORY AGENT; RAPAMYCIN; THALIDOMIDE; THALIDOMIDE DERIVATIVE; TUMOR NECROSIS FACTOR; TUMOR NECROSIS FACTOR ANTIBODY; TUMOR NECROSIS FACTOR INHIBITOR; TUMOR NECROSIS FACTOR RECEPTOR 1; ANTIINFLAMMATORY AGENT;

ALZHEIMER DISEASE; CENTRAL NERVOUS SYSTEM; DISEASE COURSE; DRUG TARGETING; GENETIC MANIPULATION; GENETIC TRANSCRIPTION; HEALTH HAZARD; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; KINESIOTHERAPY; META ANALYSIS (TOPIC); NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REPRESSOR GENE; REVIEW; RODENT MODEL; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; ANIMAL; ANTAGONISTS AND INHIBITORS; GENETICS; IMMUNOLOGY; METABOLISM;

ALZHEIMER DISEASE; ANIMALS; ANTI-INFLAMMATORY AGENTS; HUMANS; TUMOR NECROSIS FACTOR-ALPHA;

EID: 85015675352     PISSN: 15672050     EISSN: 18755828     Source Type: Journal    
DOI: 10.2174/1567205013666160930110551     Document Type: Review

References (192)

1. World Alzheimer Report. 2014; [about]. Available from: http://www.alz.co.uk/research/world-report-2014
2. Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118(1): 5-36 (2009).
3. Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, et al. Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4(3): 231-2 (2001).
4. Gertsik N, Chiu D, Li YM. Complex regulation of gamma-secretase: from obligatory to modulatory subunits. Front Aging Neurosci 6: 342 (2014).
5. Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120(3): 885-90 (1984).
6. Ikeda S, Allsop D, Glenner GG. A study of the morphology and distribution of amyloid beta protein immunoreactive plaque and related lesions in the brains of Alzheimer’s disease and adult Down’s syndrome. Prog Clin Biol Res 317: 313-23 (1989).
7. Selkoe DJ. The molecular pathology of Alzheimer’s disease. Neuron 6(4): 487-98 (1991).
8. Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12(10): 383-8 (1991).
9. Vassar R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res Ther 6(9): 89 (2014).
10. Golde TE, Koo EH, Felsenstein KM, Osborne BA, Miele L. gamma-Secretase inhibitors and modulators. Biochim Biophys Acta 1828(12): 2898-907 (2013).
11. Lannfelt L, Moller C, Basun H, Osswald G, Sehlin D, Satlin A, et al. Perspectives on future Alzheimer therapies: amyloid-beta protofibrils a new target for immunotherapy with BAN2401 in Alzheimer’s disease. Alzheimers Res Ther 6(2): 16 (2014).
12. Uro-Coste E, Russano de Paiva G, Guilbeau-Frugier C, Sastre N, Ousset PJ, da Silva NA, et al. Cerebral amyloid angiopathy and microhemorrhages after amyloid beta vaccination: case report and brief review. Clin Neuropathol 29(4): 209-16 (2010).
13. Dockens R, Wang JS, Castaneda L, Sverdlov O, Huang SP, Slemmon R, et al. A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. Clin Pharmacokin 51(10): 681-93 (2012).
14. Menting KW, Claassen JA. beta-secretase inhibitor; a promising novel therapeutic drug in Alzheimer’s disease. Front Aging Neurosci 6: 165 (2014).
15. Lahiri DK, Maloney B, Long JM, Greig NH. Lessons from a BACE1 inhibitor trial: Off-site but not off base. Alzheimers Dement 10(5): S411-9 (2014).
16. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 369(4): 341-50 (2013).
17. Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64(9): 1553-62 (2005).
18. Sadleir KR, Bennett DA, Schneider JA, Vassar R. Elevated Abeta42 in aged, non-demented individuals with cerebral atherosclerosis. Curr Alzheimer Res 10(8): 785-9 (2013).
19. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71(5): 362-81 (2012).
20. Herrup K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18(6): 794-9 (2015).
21. Musiek ES, Holtzman DM. Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat Neurosci 18(6): 800-6 (2015).
22. McGeer PL, McGeer EG. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 126(4): 479-97 (2013).
23. Boutajangout A, Wisniewski T. Tau-based therapeutic approaches for Alzheimer’s disease a mini-review. Gerontology 60(5): 381-5 (2014).
24. Encouraging Results of AXON’s Tau Vaccine Advance Alzheimer’s Therapy. 2015; [about]. Available from: http://www.reuters.com/article/2015/07/23/dc-axon-neuroscienceidUSnBw235117a+100+BSW20150723
25. Kontsekova E, Zilka N, Kovacech B, Novak P, Novak M. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther 6(4): 44 (2014).
26. Heneka MT, O’Banion MK. Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 184(1-2): 69-91 (2007).
27. Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer’s disease, role of cytokines. Sci World J 2012: 756357 (2012).
28. Jaturapatporn D, Isaac MG, McCleery J, Tabet N. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev 2: CD006378 (2012).
29. Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci 16(5): 821-47 (2013).
30. Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, et al. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 14(12): 877-82 (2013).
31. Tweedie D, Sambamurti K, Greig NH. TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets. Curr Alzheimer Res 4(4): 378-85 (2007).
32. Montgomery SL, Bowers WJ. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol 7(1): 42-59 (2012).
33. Fischer R, Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev 2015: 610813 (2015).
34. Clark IA, Alleva LM, Vissel B. The roles of TNF in brain dysfunction and disease. Pharmacol Ther 128(3): 519-48 (2010).
35. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104(4): 487-501 (2001).
36. Incorvaia C, Frati F, Verna N, D’Alo S, Motolese A, Pucci S. Allergy and the skin. Clin Exp Immunol 153(1): 27-9 (2008).
37. Bradley JR. TNF-mediated inflammatory disease. J Pathol 214(2): 149-60 (2008).
38. Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ 10(1): 45-65 (2003).
39. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, et al. A metalloproteinase disintegrin that releases tumournecrosis factor-alpha from cells. Nature 385(6618): 729-33 (1997).
40. Wang J, Al-Lamki RS. Tumor necrosis factor receptor 2: its contribution to acute cellular rejection and clear cell renal carcinoma. Biomed Res Int 2013: 821310 (2013).
41. Speeckaert MM, Speeckaert R, Laute M, Vanholder R, Delanghe JR. Tumor necrosis factor receptors: biology and therapeutic potential in kidney diseases. Am J Nephrol 36(3): 261-70 (2012).
42. MacEwan DJ. TNF ligands and receptors--a matter of life and death. Br J Pharmacol 135(4): 855-75 (2002).
43. Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harbor Perspec Biol 1(6): a001651(2009).
44. Zhang H, Yan D, Shi X, Liang H, Pang Y, Qin N, et al. Transmembrane TNF-alpha mediates “forward” and “reverse” signaling, inducing cell death or survival via the NF-kappaB pathway in Raji Burkitt lymphoma cells. J Leukoc Biol 84(3): 789-97 (2008).
45. Sriram K, O’Callaghan JP. Divergent roles for tumor necrosis factor-alpha in the brain. J Neuroimmune Pharmacol 2(2): 140-53 (2007).
46. Probert L. TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects. Neuroscience 302: 2-22 (2015).
47. Memet S. NF-kappaB functions in the nervous system: from development to disease. Biochem Pharmacol 72(9): 1180-95 (2006).
48. Kaltschmidt B, Widera D, Kaltschmidt C. Signaling via NF-kappaB in the nervous system. Biochim Biophys Acta 1745(3): 287-99 (2005).
49. Sairanen TR, Lindsberg PJ, Brenner M, Carpen O, Siren A. Differential cellular expression of tumor necrosis factor-alpha and Type I tumor necrosis factor receptor after transient global forebrain ischemia. J Neurol Sci 186(1-2): 87-99 (2001).
50. Gong C, Qin Z, Betz AL, Liu XH, Yang GY. Cellular localization of tumor necrosis factor alpha following focal cerebral ischemia in mice. Brain Res 801(1-2): 1-8 (1998).
51. Badoer E. Microglia: activation in acute and chronic inflammatory states and in response to cardiovascular dysfunction. Int J Biochem Cell Biol 42(10): 1580-5 (2010).
52. Pan W, Kastin AJ. Penetration of neurotrophins and cytokines across the blood-brain/blood-spinal cord barrier. Adv Drug Deliv Rev 36(2-3): 291-98 (1999).
53. Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 2(4): 241-8 (1995).
54. Pan W, Kastin AJ. TNFalpha transport across the blood-brain barrier is abolished in receptor knockout mice. Exp Neurol 174(2): 193-200 (2002).
55. Banks WA, Farr SA, Morley JE. Entry of blood-borne cytokines into the central nervous system: effects on cognitive processes. Neuroimmunomodulation 10(6): 319-27 (2002).
56. Engelhardt B. Regulation of immune cell entry into the central nervous system. Results Probl Cell Differ 43: 259-80 (2006).
57. Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med 3(10): 136 (2015).
58. Poon VY, Choi S, Park M. Growth factors in synaptic function. Front Synaptic Neurosci 5: 6 (2013).
59. McAfoose J, Baune BT. Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev 33(3): 355-66 (2009).
60. Santello M, Bezzi P, Volterra A. TNFalpha controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69(5): 988-1001 (2011).
61. Rao JS, Kellom M, Kim HW, Rapoport SI, Reese EA. Neuroin-flammation and synaptic loss. Neurochem Res 37(5): 903-10 (2012).
62. Park KM, Bowers WJ. Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal 22(7): 977-83 (2010).
63. Olmos G, Llado J. Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity. Mediat Inflamm 2014: 861231 (2014).
64. Plant SR, Arnett HA, Ting JP. Astroglial-derived lymphotoxin-alpha exacerbates inflammation and demyelination, but not remyelination. Glia 49(1): 1-14 (2005).
65. Krueger JM. The role of cytokines in sleep regulation. Curr Pharm Des 14(32): 3408-16 (2008).
66. Plata-Salaman CR. Cytokines and feeding. Int J Obes Relat Metab Disord 25(5): S48-52 (2001).
67. Cacci E, Claasen JH, Kokaia Z. Microglia-derived tumor necrosis factor-alpha exaggerates death of newborn hippocampal progenitor cells in vitro. J Neurosci Res 80(6): 789-97 (2005).
68. Iosif RE, Ahlenius H, Ekdahl CT, Darsalia V, Thored P, Jovinge S, et al. Suppression of stroke-induced progenitor proliferation in adult subventricular zone by tumor necrosis factor receptor 1. J Cereb Blood Flow Metab 28(9): 1574-87 (2008).
69. Plata-Salaman CR. Brain cytokines and disease. Acta Neuropsy-chiatrica 14: 262-78 (2002).
70. Liao YF, Wang BJ, Cheng HT, Kuo LH, Wolfe MS. Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J Biol Chem 279(47): 49523-32 (2004).
71. Lahiri DK, Chen D, Vivien D, Ge YW, Greig NH, Rogers JT. Role of cytokines in the gene expression of amyloid beta-protein precursor: identification of a 5’-UTR-binding nuclear factor and its implications in Alzheimer’s disease. J Alzheimers Dis 5(2): 81-90 (2003).
72. 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 13(1): 63-8 (1999).
73. McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 5: 45 (2008).
74. Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol 36(6): 361-5 (2007).
75. Na KS, Jung HY, Kim YK. The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuro-psychopharmacol Biol Psychiatry 48: 277-86 (2014).
76. Brabers NA, Nottet HS. Role of the pro-inflammatory cytokines TNF-alpha and IL-1beta in HIV-associated dementia. Eur J Clin Invest 36(7): 447-58 (2006).
77. Brosseron F, Krauthausen M, Kummer M, Heneka MT. Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview. Mol Neurobiol 50(2): 534-44 (2014).
78. Tarkowski E, Liljeroth AM, Minthon L, Tarkowski A, Wallin A, Blennow K. Cerebral pattern of proand anti-inflammatory cytokines in dementias. Brain Res Bull 61(3): 255-60 (2003).
79. Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68(10): 930-41 (2010).
80. O’Bryant SE, Gupta V, Henriksen K, Edwards M, Jeromin A, Lista S, et al. Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer’s disease research. Alzheimers Dement 11(5): 549-60 (2015).
81. Magaki S, Mueller C, Dickson C, Kirsch W. Increased production of inflammatory cytokines in mild cognitive impairment. Exp Gerontol 42(3): 233-40 (2007).
82. Zhao M, Cribbs DH, Anderson AJ, Cummings BJ, Su JH, Wasserman AJ, et al. The induction of the TNFalpha death domain signaling pathway in Alzheimer’s disease brain. Neurochem Res 28(2): 307-18 (2003).
83. Pyo H, Jou I, Jung S, Hong S, Joe EH. Mitogen-activated protein kinases activated by lipopolysaccharide and beta-amyloid in cultured rat microglia. Neuroreport 9(5): 871-4 (1998).
84. Dhawan G, Floden AM, Combs CK. Amyloid-beta oligomers stimulate microglia through a tyrosine kinase dependent mechanism. Neurobiol Aging 33(10): 2247-61 (2012).
85. Lue LF, Walker DG, Rogers J. Modeling microglial activation in Alzheimer’s disease with human postmortem microglial cultures. Neurobiol Aging 22(6): 945-56 (2001).
86. Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, et al. Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol 173(6): 1768-82 (2008).
87. Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94(24): 13287-92 (1997).
88. McAlpine FE, Tansey MG. Neuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease. J Inflamm Res 1: 29-39 (2008).
89. Neta R, Sayers TJ, Oppenheim JJ. Relationship of TNF to interleukins. Immunol Series 56: 499-566 (1992).
90. Zhao J, O’Connor T, Vassar R. The contribution of activated astrocytes to Abeta production: implications for Alzheimer’s disease pathogenesis. J Neuroinflammation 8: 150 (2011).
91. Patel JR, Brewer GJ. Age-related changes to tumor necrosis factor receptors affect neuron survival in the presence of beta-amyloid. J Neurosci Res 86(10): 2303-13 (2008).
92. Koenigsknecht-Talboo J, Landreth GE. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci 25(36): 8240-9 (2005).
93. Yoshiyama Y, Kojima A, Itoh K, Uchiyama T, Arai K. Anticho-linergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model. Neurobiol Dis 45(1): 329-36 (2012).
94. Montgomery SL, Narrow WC, Mastrangelo MA, Olschowka JA, O’Banion MK, Bowers WJ. Chronic neuronand age-selective down-regulation of TNF receptor expression in triple-transgenic Alzheimer disease mice leads to significant modulation of amyloidand Tau-related pathologies. Am J Pathol 182(6): 2285-97 (2013).
95. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 94(7): 3195-9 (1997).
96. Baseggio L, Bartholin L, Chantome A, Charlot C, Rimokh R, Salles G. Allele-specific binding to the -308 single nucleotide polymorphism site in the tumour necrosis factor-alpha promoter. Eur J Immunogenet 31(1): 15-9 (2004).
97. Ghaderian SM, Akbarzadeh Najar R, Tabatabaei Panah AS. Tumor necrosis factor-alpha: investigation of gene polymorphism and regulation of TACE-TNF-alpha system in patients with acute myocardial infarction. Mol Biol Rep 38(8): 4971-7 (2011).
98. Wang T. TNF-alpha G308A polymorphism and the susceptibility to Alzheimer’s disease: an updated meta-analysis. Arch Med Res 46(1): 24-30 e1 (2015).
99. Alvarez V, Mata IF, Gonzalez P, Lahoz CH, Martinez C, Pena J, et al. Association between the TNFalpha-308 A/G polymorphism and the onset-age of Alzheimer disease. Am J Med Genet 114(5): 574-7 (2002).
100. Do Carmo S, Cuello AC. Modeling Alzheimer’s disease in transgenic rats. Mol Neurodegener 8: 37 (2013).
101. Hall AM, Roberson ED. Mouse models of Alzheimer’s disease. Brain Res Bull 88(1): 3-12 (2012).
102. Cavanaugh SE, Pippin JJ, Barnard ND. Animal models of Alzheimer disease: historical pitfalls and a path forward. ALTEX 31(3): 279-302 (2014).
103. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39(3): 409-21 (2003).
104. He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 178(5): 829-41 (2007).
105. McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis 34(1): 163-77 (2009).
106. Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4(1): 97-100 (1998).
107. Shi JQ, Shen W, Chen J, Wang BR, Zhong LL, Zhu YW, et al. Anti-TNF-alpha reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res 1368: 239-47 (2011).
108. Detrait ER, Danis B, Lamberty Y, Foerch P. Peripheral administration of an anti-TNF-alpha receptor fusion protein counteracts the amyloid induced elevation of hippocampal TNF-alpha levels and memory deficits in mice. Neurochem Intern 72: 10-3 (2014).
109. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem 285(17): 13107-20 (2010).
110. Seabrook TJ, Jiang L, Maier M, Lemere CA. Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice. Glia 53(7): 776-82 (2006).
111. Li C, Yuan K, Schluesener H. Impact of minocycline on neurodegenerative diseases in rodents: a meta-analysis. Rev Neurosci 24(5): 553-62 (2013).
112. Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Park CH, et al. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models. Neuropsychopharmacol 32(11): 2393-404 (2007).
113. Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer’s disease-like amyloid pathology. J Neuroinflammation 9: 62 (2012).
114. Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 177(6): 1675-80 (1993).
115. Alkam T, Nitta A, Mizoguchi H, Saito K, Seshima M, Itoh A, et al. Restraining tumor necrosis factor-alpha by thalidomide prevents the amyloid beta-induced impairment of recognition memory in mice. Behav Brain Res 189(1): 100-6 (2008).
116. Gabbita SP, Srivastava MK, Eslami P, Johnson MF, Kobritz NK, Tweedie D, et al. Early intervention with a small molecule inhibitor for tumor nefosis factor-alpha prevents cognitive deficits in a triple transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 9: 99 (2012).
117. Tweedie D, Ferguson RA, Fishman K, Frankola KA, Van Praag H, Holloway HW, et al. Tumor necrosis factor-alpha synthesis inhibitor 3,6’-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease. J Neuroinflammation 9: 106 (2012).
118. Allison AC, Cacabelos R, Lombardi VR, Alvarez XA, Vigo C. Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 25(7): 1341-57 (2001).
119. McGowan E, Sanders S, Iwatsubo T, Takeuchi A, Saido T, Zehr C, et al. Amyloid phenotype characterization of transgenic mice overexpressing both mutant amyloid precursor protein and mutant presenilin 1 transgenes. Neurobiol Dis 6(4): 231-44 (1999).
120. Paris D, Ganey NJ, Laporte V, Patel NS, Beaulieu-Abdelahad D, Bachmeier C, et al. Reduction of beta-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 7: 17 (2010).
121. Lizzul PF, Aphale A, Malaviya R, Sun Y, Masud S, Dombrovskiy V, et al. Differential expression of phosphorylated NFkappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept. J Invest Dermatol 124(6): 1275-83 (2005).
122. Guidi L, Costanzo M, Ciarniello M, De Vitis I, Pioli C, Gatta L, et al. Increased levels of NF-kappaB inhibitors (IkappaBalpha and IkappaBgamma) in the intestinal mucosa of Crohn’s disease patients during infliximab treatment. Int J Immunopathol Pharmacol 18(1): 155-64 (2005).
123. Noman AS, Koide N, Hassan F, I IE-K, Dagvadorj J, Tumurkhuu G, et al. Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production via down-regulation of MyD88 expression. Innate Immun 15(1): 33-41 (2009).
124. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 22(3): 659-61 (2008).
125. Blanchard OL, Smoliga JM. Translating dosages from animal models to human clinical trials--revisiting body surface area scaling. FASEB J 29(5): 1629-34 (2015).
126. Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 70(19): 1672-7 (2008).
127. Tobinick EL, Gross H. Rapid cognitive improvement in Alz-heimer’s disease following perispinal etanercept administration. J Neuroinflammation 5: 2 (2008).
128. Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother 10(6): 985-1002 (2010).
129. Zhou QH, Sumbria R, Hui EK, Lu JZ, Boado RJ, Pardridge WM. Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor. J Pharmacol Exp Ther 339(2): 618-23 (2011).
130. Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. Med Gen Med 8(2): 25 (2006).
131. Roerink ME, Groen RJ, Franssen G, Lemmers-van de Weem B, Boerman OC, van der Meer JW. Central delivery of iodine-125-labeled cetuximab, etanercept and anakinra after perispinal injection in rats: possible implications for treating Alzheimer’s disease. Alzheimers Res Ther 7(1): 70 (2015).
132. Tobinick EL, Chen K, Chen X. Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging. BMC Res Notes 2: 28 (2009).
133. Zahs KR, Ashe KH. ‘Too much good news’ are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer’s disease? Trends Neurosci 33(8): 381-9 (2010).
134. Ferretti MT, Cuello AC. Does a pro-inflammatory process precede Alzheimer’s disease and mild cognitive impairment? Curr Alz-heimer Res 8(2): 164-74 (2011).
135. Brandt C, Pedersen BK. The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases. J Biomed Biotechnol 2010: 520258 (2010).
136. Pedersen BK, Bruunsgaard H. Possible beneficial role of exercise in modulating low-grade inflammation in the elderly. Scand J Med Sci Sports 13(1): 56-62 (2003).
137. Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol 103(3): 1093-8 (2007).
138. Pedersen BK, Fischer CP. Physiological roles of muscle-derived interleukin-6 in response to exercise. Curr Opin Clin Nutr Metab Care 10(3): 265-71 (2007).
139. Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J 17(8): 884-6 (2003).
140. Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK. Proand anti-inflammatory cytokine balance in strenuous exercise in humans. J Physiol 515 (Pt 1): 287-91 (1999).
141. Nascimento CM, Pereira JR, de Andrade LP, Garuffi M, Talib LL, Forlenza OV, et al. Physical exercise in MCI elderly promotes reduction of pro-inflammatory cytokines and improvements on cognition and BDNF peripheral levels. Curr Alzheimer Res 11(8): 799-805 (2014).
142. Nascimento CM, Pereira JR, Pires de Andrade L, Garuffi M, Ayan C, Kerr DS, et al. Physical exercise improves peripheral BDNF levels and cognitive functions in mild cognitive impairment elderly with different bdnf Val66Met genotypes. J Alzheimers Dis 43(1): 81-91 (2015).
143. Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA. Correlations and interactions in the production of inter-leukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 75(1): 40-7 (1990).
144. Igaz P, Horvath A, Horvath B, Szalai C, Pallinger E, Rajnavolgyi E, et al. Soluble interleukin-6 receptor (sIL-6R) makes IL-6R negative T cell line respond to IL-6; it inhibits TNF production. Immunol Lett 71(3): 143-8 (2000).
145. Roach KE, Tappen RM, Kirk-Sanchez N, Williams CL, Loewenstein D. A randomized controlled trial of an activity specific exercise program for individuals with Alzheimer disease in long-term care settings. J Geriatr Phys Ther 34(2): 50-6 (2011).
146. Benveniste EN, Tang LP, Law RM. Differential regulation of astrocyte TNF-alpha expression by the cytokines TGF-beta, IL-6 and IL-10. Int J Dev Neurosci 13(3-4): 341-9 (1995).
147. Steensberg A, Fischer CP, Keller C, Moller K, Pedersen BK. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab 285(2): E433-7 (2003).
148. Edens HA, Parkos CA. Modulation of epithelial and endothelial paracellular permeability by leukocytes. Adv Drug Deliv Rev 41(3): 315-28 (2000).
149. Cronstein BN, Kimmel SC, Levin RI, Martiniuk F, Weissmann G. A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci USA 89(21): 9991-5 (1992).
150. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101(15): 1767-72 (2000).
151. Zuliani G, Volpato S, Ble A, Bandinelli S, Corsi AM, Lauretani F, et al. High interleukin-6 plasma levels are associated with low HDL-C levels in community-dwelling older adults: the InChianti study. Atherosclerosis 192(2): 384-90 (2007).
152. Jain SK, Kannan K, Lim G, Matthews-Greer J, McVie R, Bocchini JA, Jr. Elevated blood interleukin-6 levels in hyperketonemic type 1 diabetic patients and secretion by acetoacetate-treated cultured U937 monocytes. Diabetes Care 26(7): 2139-43 (2003).
153. Tracey KJ. Reflex control of immunity. Nat Rev Immunol 9(6): 418-28 (2009).
154. 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 405(6785): 458-62 (2000).
155. Pohanka M. Alpha7 nicotinic acetylcholine receptor is a target in pharmacology and toxicology. Int J Mol Sci 13(2): 2219-38 (2012).
156. Nizri E, Brenner T. Modulation of inflammatory pathways by the immune cholinergic system. Amino Acids 45(1): 73-85 (2013).
157. Hu W, Gray NW, Brimijoin S. Amyloid-beta increases acetylcho-linesterase expression in neuroblastoma cells by reducing enzyme degradation. J Neurochem 86(2): 470-8 (2003).
158. Reale M, Di Nicola M, Velluto L, D’Angelo C, Costantini E, Lahiri DK, et al. Selective acetyland butyrylcholinesterase inhibitors reduce amyloid-beta ex vivo activation of peripheral chemo-cytokines from Alzheimer’s disease subjects: exploring the cholinergic antiinflammatory pathway. Curr Alzheimer Res 11(6): 608-22 (2014).
159. Pavlov VA, Parrish WR, Rosas-Ballina M, Ochani M, Puerta M, Ochani K, et al. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav Immun 23(1): 41-5 (2009).
160. Butchart J, Brook L, Hopkins V, Teeling J, Puntener U, Culliford D, et al. Etanercept in Alzheimer disease: A randomized, placebocontrolled, double-blind, phase 2 trial. Neurology 84(21): 2161-68 (2015).
161. Frautschy SA, Cole GM. Why pleiotropic interventions are needed for Alzheimer’s disease. Mol Neurobiol 41(2-3): 392-409 (2010).
162. Atigari OV, Healy D. Schizophrenia-like disorder associated with etanercept treatment. BMJ Case Reports 2014: (2014).
163. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 344(12): 907-16 (2001).
164. Deepak P, Stobaugh DJ, Sherid M, Sifuentes H, Ehrenpreis ED. Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System. Aliment Pharmacol Ther 38(4): 388-96 (2013).
165. Poduslo JF, Curran GL. Amyloid beta peptide as a vaccine for Alzheimer’s disease involves receptor-mediated transport at the blood-brain barrier. Neuroreport 12(15): 3197-200 (2001).
166. Richter F, Liebig T, Guenzi E, Herrmann A, Scheurich P, Pfizen-maier K, et al. Antagonistic TNF receptor one-specific antibody (ATROSAB): receptor binding and in vitro bioactivity. PLoS One 8(8): e72156 (2013).
167. Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 148(3): 245-54 (2006).
168. Dziedzic T, Wybranska I, Dembinska-Kiec A, Klimkowicz A, Slowik A, Pankiewicz J, et al. Dexamethasone inhibits TNF-alpha synthesis more effectively in Alzheimer’s disease patients than in healthy individuals. Dement Geriatr Cogn Disord 16(4): 283-6 (2003).
169. Alten R, Wiebe E. Hypothalamic-pituitary-adrenal axis function in patients with rheumatoid arthritis treated with different glucocorticoid approaches. Neuroimmunomodulation 22(1-2): 83-8 (2015).
170. Greig NH, Giordano T, Zhu X, Yu QS, Perry TA, Holloway HW, et al. Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases. Acta Neurobiol Exp (Wars) 64(1): 1-9 (2004).
171. Crane E, List A. Immunomodulatory drugs. Cancer Invest 23(7): 625-34 (2005).
172. Monson NL, Ireland SJ, Ligocki AJ, Chen D, Rounds WH, Li M, et al. Elevated CNS inflammation in patients with preclinical Alzheimer’s disease. J Cereb Blood Flow Metab 34(1): 30-3 (2014).
173. Luo W, Yu QS, Salcedo I, Holloway HW, Lahiri DK, Brossi A, et al. Design, synthesis and biological assessment of novel Nsubstituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines and 3-substituted 2,6-dioxopiperidines for TNF-alpha inhibitory activity. Bioorg Med Chem 19(13): 3965-72 (2011).
174. Zhu X, Giordano T, Yu QS, Holloway HW, Perry TA, Lahiri DK, et al. Thiothalidomides: novel isosteric analogues of thalidomide with enhanced TNF-alpha inhibitory activity. J Med Chem 46(24): 5222-9 (2003).
175. Masri MA. The mosaic of immunosuppressive drugs. Mol Immunol 39 (17-18): 1073-7 (2003).
176. Cao W, Konsolaki M. FKBP immunophilins and Alzheimer’s disease: a chaperoned affair. J Biosci 36(3): 493-8 (2011).
177. Azzi JR, Sayegh MH, Mallat SG. Calcineurin inhibitors: 40 years later, can’t live without. J Immunol 191(12): 5785-91 (2013).
178. Lee RK, Knapp S, Wurtman RJ. Prostaglandin E2 stimulates amyloid precursor protein gene expression: inhibition by immunosuppressants. J Neurosci 19(3): 940-7 (1999).
179. Begley DJ, Squires LK, Zlokovic BV, Mitrovic DM, Hughes CC, Revest PA, et al. Permeability of the blood-brain barrier to the immunosuppressive cyclic peptide cyclosporin A. J Neurochem 55(4): 1222-30 (1990).
180. Eidelman BH, Abu-Elmagd K, Wilson J, Fung JJ, Alessiani M, Jain A, et al. Neurologic complications of FK 506. Transplant Proc 23(6): 3175-8.(1991).
181. Wijdicks EF. Neurotoxicity of immunosuppressive drugs. Liver Transpl 7(11): 937-42 (2001).
182. Powell JD, Lerner CG, Schwartz RH. Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. J Immunol 162(5): 2775-84 (1999).
183. Luo H, Chen H, Daloze P, Chang JY, St-Louis G, Wu J. Inhibition of in vitro immunoglobulin production by rapamycin. Transplantation 53(5): 1071-6 (1992).
184. Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando) 28(3): 126-33 (2014).
185. Suriano AR, Sanford AN, Kim N, Oh M, Kennedy S, Henderson MJ, et al. GCF2/LRRFIP1 represses tumor necrosis factor alpha expression. Mol Cell Biol 25(20): 9073-81 (2005).
186. Gubern C, Camos S, Hurtado O, Rodriguez R, Romera VG, Sobrado M, et al. Characterization of Gcf2/Lrrfip1 in experimental cerebral ischemia and its role as a modulator of Akt, mTOR and beta-catenin signaling pathways. Neuroscience 268: 48-65 (2014).
187. Ariake K, Ohtsuka H, Motoi F, Douchi D, Oikawa M, Rikiyama T, et al. GCF2/LRRFIP1 promotes colorectal cancer metastasis and liver invasion through integrin-dependent RhoA activation. Cancer Lett 325(1): 99-107 (2012).
188. Butchart J, Brook L, Hopkins V, Teeling J, Puntener U, Culliford D, et al. Etanercept in Alzheimer disease: a randomized, placebocontrolled, double-blind, phase 2 trial. Neurology 84(21): 2161-8 (2015).
189. Montgomery SL, Mastrangelo MA, Habib D, Narrow WC, Knowlden SA, Wright TW, et al. Ablation of TNF-RI/RII expression in Alzheimer’s disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-alpha suppressive therapeutic strategies in the brain. Am J Pathol 179(4): 2053-70 (2011).
190. Solomon AJ, Spain RI, Kruer MC, Bourdette D. Inflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors. Multiple Sclerosis 17(12): 1472-87 (2011).
191. Kaltsonoudis E, Voulgari PV, Konitsiotis S, Drosos AA. Demyelination and other neurological adverse events after anti-TNF therapy. Autoimmun Rev 13(1): 54-8 (2014).
192. Nozaki K, Silver RM, Stickler DE, Abou-Fayssal NG, Giglio P, Kamen DL, et al. Neurological deficits during treatment with tumor necrosis factor-alpha antagonists. Am J Med Sci 342(5): 352-5 (2011).