Tumor necrosis factor-α synthesis inhibitor 3,6′-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease

Journal of Neuroinflammation

Susanna Rosi²  Nigel H Greig⁵  Francesca Bosetti¹  Debomoy K Lahiri³  Balmiki Ray³  Sergio Barlati⁷  Isabella Russo⁶  Luca Caracciolo⁶  Yazhou Li⁵  Weiming Luo⁵  Harold W Holloway⁵  Henriette Van Praag⁵  Kathryn A Frankola⁵  Kelly Fishman⁴  Ryan A Ferguson⁴  David Tweedie⁵ 

[1] National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA;Departments of Physical Therapy Rehabilitation Science and Neurological Surgery, University of California, San Francisco, CA, USA;Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research Indiana University School of Medicine, Indianapolis, IN, 46202, USA;Brain and Spinal Injury Center, University of California, San Francisco, CA, 94143, USA;Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA;Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA;Division of Biology & Genetics, Department of Biomedical Sciences and Biotechnologies & National Institute of Neuroscience, University of Brescia, Brescia, 25123, Italy

关键词: Lenalidomide;    Thalidomide;    Tau;    Amyoid-β peptide;    Mild cognitive impairment;    Alzheimer’s disease;    Neuroprotection;    TNF-α;    Neurodegeneration;    Neuroinflammation;   

Others  :  1212583
DOI  :  10.1186/1742-2094-9-106

 received in 2012-03-14, accepted in 2012-05-29,  发布年份 2012

【 摘 要 】

Background

Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer’s disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.

Methods

The potential benefits of a novel TNF-α-lowering agent, 3,6′-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ_1–42 challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6′-dithiothaliodmide.

Results

3,6′-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with Aβ_1–42 peptide, prior systemic 3,6′-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6′-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment.

Conclusions

Our data suggest a strong beneficial effect of 3,6′-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.

【 授权许可】

   
2012 Tweedie et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]McGeer PL, Itagaki S, Boyes BE, McGeer EG: Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 1988, 38:1285-1291.
• [2]Hirsch EC, Hunot S, Damier P, Faucheux B: Glial cells and inflammation in Parkinson’s disease: a role in neurodegeneration? Ann Neurol 1988, 44:S115-S120.
• [3]Nagatsu T, Mogi M, Ichinose H, Togari A: Cytokines in Parkinson’s disease. J Neural Transm Suppl 2000, 58:143-151.
• [4]Liu B, Hong JS: Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 2003, 304:1-7.
• [5]Tweedie D, Sambamurti K, Greig NH: TNF-α inhibition as a treatment strategy for neurodegenerative disorders: New drug candidates and targets. Curr Alzheimer Res 2007, 4:378-385.
• [6]Frankola KA, Greig NH, Luo W, Tweedie D: Targeting TNF-α to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS Neurol Disord Drug Targets 2011, 10:391-403.
• [7]Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP: The role of glial reaction and inflammation in Parkinson’s disease. Ann NY Acad Sci 2003, 991:214-228.
• [8]Sawada M, Imamura K, Nagatsu T: Role of cytokines in inflammatory process in Parkinson’s disease. J Neural Transm Suppl 2006, 70:373-381.
• [9]Tansey MG, Frank-Cannon TC, McCoy MK, Lee JK, Martinez TN, McAlpine FE, Ruhn KA, Tran TA: Neuroinflammation in Parkinson’s disease: is there sufficient evidence for mechanism-based interventional therapy? Front Biosci 2008, 13:709-717.
• [10]McCoy MK, Tansey MG: TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 2008, 5:45. BioMed Central Full Text
• [11]Watters O, O’Connor JJ: A role for tumor necrosis factor-α in ischemia and ischemic preconditioning. J Neuroinflammation 2011, 8:87. BioMed Central Full Text
• [12]Hallenbeck JM: The many faces of tumor necrosis factor in stroke. Nat Med 2002, 8:1363-1368.
• [13]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 2003, 5:81-90.
• [14]Sambamurti K, Greig NH, Lahiri DK: Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer’s disease. Neuromolecular Med 2002, 1:1-31.
• [15]Sastre M, Richardson JC, Gentleman SM, Brooks DJ: Inflammatory risk factors and pathologies associated with Alzheimer’s disease. Curr Alzheimer Res 2011, 8:132-141.
• [16]Braak H, Braak E: Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991, 82:239-259.
• [17]Rosi S, Ramirez-Amaya V, Vazdarjanova A, Worley PF, Barnes CA, Wenk GL: Neuroinflammation alters the hippocampal pattern of behaviorally induced Arc expression. J Neurosci 2005, 25:723-731.
• [18]Rosi S, Vazdarjanova A, Ramirez-Amaya V, Worley PF, Barnes CA, Wenk GL: Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neuroscience 2006, 142:1303-1315.
• [19]Bonow RH, Aïd S, Zhang Y, Becker KG, Bosetti F: The brain expression of genes involved in inflammatory response, the ribosome, and learning and memory is altered by centrally injected lipopolysaccharide in mice. Pharmacogenomics J 2009, 9:116-126.
• [20]Hauss-Wegrzyniak B, Lynch MA, Vraniak PD, Wenk GL: Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses. Exp Neurol 2002, 176:336-341.
• [21]Rosi S, Ramirez-Amaya V, Vazdarjanova A, Esparza EE, Larkin PB, Fike JR, Wenk GL, Barnes CA: Accuracy of hippocampal network activity is disrupted by neuroinflammation: rescue by memantine. Brain 2009, 132:2464-2477.
• [22]Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM: Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003, 39:409-421.
• [23]Janelsins MC, Mastrangelo MA, Oddo S, LaFerla FM, Federoff HJ, Bowers WJ: Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer’s disease mice. J Neuroinflammation 2005, 2:23. BioMed Central Full Text
• [24]Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, LaFerla FM, Callahan LM, Federoff HJ, Bowers WJ: 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 2008, 173:1768-1782.
• [25]McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, Das P, Golde TE, LaFerla FM, Oddo S, Blesch A, Tansey MG: Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis 2009, 34:163-177.
• [26]Fonseca MI, Ager RR, Chu SH, Yazan O, Sanderson SD, LaFerla FM, Taylor SM, Woodruff TM, Tenner AJ: Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer’s disease. J Immunol 2009, 183:1375-1383.
• [27]Zhu X, Giordano T, Yu Q-S, Holloway HW, Perry T, Lahiri DK, Brossi A, Greig NH: Thiothalidomides: Novel isosteric analogs of thalidomide with enhanced TNF-α inhibitory activity. J Med Chem 2003, 46:5222-5229.
• [28]Tweedie D, Frankola KA, Luo W, Li Y, Greig NH: Thalidomide analogues suppress lipopolysaccharide-induced synthesis of TNF-α and nitrite, an intermediate of nitric oxide, in a cellular model of inflammation. Open Biochem J 2011, 5:37-44.
• [29]Belarbi K, Jopson T, Tweedie D, Arellano C, Luo W, Greig NH, Rosi S: TNF-alpha protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J Neuroinflammation 2012, 9:23. BioMed Central Full Text
• [30]Baratz R, Tweedie D, Rubovitch V, Luo W, Yoon JS, Hoffer BJ, Greig NH, Pick CG: Tumor necrosis factor-α synthesis inhibitor, 3,6′-dithiothalidomide, reverses behavioral impairments induced by minimal traumatic brain injury in mice. J Neurochem 2011, 118:1032-1042.
• [31]Tweedie D, Luo W, Short RG, Brossi A, Holloway HW, Li Y, Yu QS, Greig NH: A cellular model of inflammation for identifying TNF-alpha synthesis inhibitors. J Neurosci Methods 2009, 183:182-187.
• [32]Choi SH, Bosetti F: Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid. Aging 2009, 1:234-244.
• [33]Schmued LC, Hopkins KJ: Fluoro-Jade: novel fluorochromes for detecting toxicant-induced neuronal degeneration. Toxicol Pathol 2000, 28:91-99.
• [34]El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD: Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 2007, 13:432-438.
• [35]Bailey JA, Ray B, Greig NH, Lahiri DK: Rivastigmine lowers Aβ and increases sAPPα levels, which parallel elevated synaptic markers and metabolic activity in degenerating primary rat neurons. PLoS One 2011, 6(7):e21954.
• [36]Li Y, Duffy KB, Ottinger MA, Ray B, Bailey JA, Holloway HW, Tweedie D, Perry T, Mattson MP, Kapogiannis D, Sambamurti K, Lahiri DK, Greig NH: GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer’s disease. J Alzheimers Dis 2010, 19:1205-1219.
• [37]Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF, Barnes CA: Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J Neurosci 2000, 20:3993-4001.
• [38]Plath N, Ohana O, Dammermann B, Errington ML, Schmitz D, Gross C, Mao X, Engelsberg A, Mahlke C, Welzl H, Kobalz U, Stawrakakis A, Fernandez E, Waltereit R, Bick-Sander A, Therstappen E, Cooke SF, Blanquet V, Wurst W, Salmen B, Bösl MR, Lipp HP, Grant SG, Bliss TV, Wolfer DP, Kuhl D: Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 2006, 52:437-444.
• [39]Rosi S: Neuroinflammation and the plasticity-related immediate-early gene Arc. Brain Behav Immun 2011, 1(Suppl):S39-S49.
• [40]Rosi S, Ramirez-Amaya V, Hauss-Wegrzyniak B, Wenk GL: Chronic brain inflammation leads to a decline in hippocampal NMDA-R1 receptors. J Neuroinflammation 2004, 1:12. BioMed Central Full Text
• [41]Maurice T, Lockhart BP, Privat A: Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. Brain Res 1996, 706:181-193.
• [42]Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F, Tsukagoshi-Nagai H, Horikoshi-Sakuraba Y, Mughal M, Rebeck GW, LaFerla FM, Mattson MP, Iwata N, Saido TC, Klein WL, Duff KE, Aisen PS, Matsuoka Y: Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res 2008, 1216:92-103.
• [43]Tarkowski E, Blennow K, Wallin A, Tarkowski A: Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol 1999, 19:223-230.
• [44]Tarkowski E, Andreasen N, Tarkowski A, Blennow K: Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2003, 74:1200-1205.
• [45]Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM: Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 2005, 45:675-688.
• [46]Perry RT, Collins JS, Wiener H, Acton R, Go RC: The role of TNF and its receptors in Alzheimer’s disease. Neurobiol Aging 2001, 22:873-883.
• [47]Laws SM, Perneczky R, Wagenpfeil S, Müller U, Förstl H, Martins RN, Kurz A, Riemenschneider M: TNF polymorphisms in Alzheimer disease and functional implications on CSF beta-amyloid levels. Hum Mutat 2005, 26:29-35.
• [48]Ramos EM, Lin MT, Larson EB, Maezawa I, Tseng LH, Edwards KL, Schellenberg GD, Hansen JA, Kukull WA, Jin LW: Tumor necrosis factor alpha and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease. Arch Neurol 2006, 63:1165-1169.
• [49]Aleong R, Blain JF, Poirier J: Pro-inflammatory cytokines modulate glial apolipoprotein E secretion. Curr Alzheimer Res 2008, 5:33-37.
• [50]He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, Staufenbiel M, Li R, Shen Y: Deletion of tumor necrosis factor death receptor inhibits amyloid-β generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 2007, 178:829-841.
• [51]Tobinick E: Tumour necrosis factor modulation for treatment of Alzheimer's disease: rationale and current evidence. CNS Drugs 2009, 23:713-725.
• [52]Tobinick E: Deciphering the physiology underlying the rapid clinical effects of perispinal etanercept in Alzheimer’s disease. Curr Alzheimer Res 2012, 9:99-109.
• [53]Lin J, Ziring D, Desai S, Kim S, Wong M, Korin Y, Braun J, Reed E, Gjertson D, Singh RR: TNF-α blockade in human diseases: an overview of efficacy and safety. Clin Immunol 2008, 126:13-30.
• [54]Tobinick EL, Gross H: Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation 2008, 5:2. BioMed Central Full Text
• [55]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 1993, 177:1675-1680.
• [56]Abdelmohsen K, Kuwano Y, Kim HH, Gorospe M: Posttranscriptional gene regulation by RNA-binding proteins during oxidative stress: implications for cellular senescence. Biol Chem 2008, 389:243-255.
• [57]Stamou P, Kontoyiannis DL: Posttranscriptional regulation of TNF mRNA: a paradigm of signal-dependent mRNA utilization and its relevance to pathology. Curr Dir Autoimmun 2010, 11:61-79.
• [58]Patil CS, Liu M, Zhao W, Coatney DD, Li F, VanTubergen EA, D’Silva NJ, Kirkwood KL: Targeting mRNA stability arrests inflammatory bone loss. Mol Ther 2008, 16:1657-1664.
• [59]Khera TK, Dick AD, Nicholson LB: Mechanisms of TNFalpha regulation in uveitis: focus on RNA-binding proteins. Prog Retin Eye Res 2010, 29:610-621.
• [60]Greig NH, Giordano T, Zhu X, Yu QS, Perry TA, Holloway HW, Brossi A, Rogers JT, Sambamurti K, Lahiri DK: Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases. Acta Neurobiol Exp 2004, 64:1-9.
• [61]Mönning U, Sandbrink R, Banati RB, Masters CL, Beyreuther K: Transforming growth factor beta mediates increase of mature transmembrane amyloid precursor protein in microglial cells. FEBS Lett 1994, 342:267-272.
• [62]Park KM, Bowers WJ: Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal 2010, 22:977-983.
• [63]Avramovich Y, Amit T, Youdim MB: Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloidogenic precursor protein. J Biol Chem 2002, 277:31466-31473.
• [64]Rosi S: Neuroinflammation and the plasticity-related immediate-early gene Arc. Brain Behav Immun 2011, 25(Suppl 1):S39-S49.
• [65]Korb E, Finkbeiner S: Arc in synaptic plasticity: from gene to behavior. Trends Neurosci 2011, 34:591-598.
• [66]Kawai T, Adachi O, Ogawa T, Takeda K, Akira S: Unresponsiveness of MyD88- deficient mice to endotoxin. Immunity 1999, 11:115-122.
• [67]Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ: Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 2008, 14:837-842.
• [68]Ashe KH, Zahs KR: Probing the biology of Alzheimer’s disease in mice. Neuron 2010, 66:631-645.
• [69]Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL: Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 2007, 27:796-807.
• [70]Yankner BA: The pathogenesis of Alzheimer’s disease. Is amyloid beta-protein the beginning or the end? Ann N Y Acad Sci 2000, 924:26-28.
• [71]Qiao X, Cummins DJ, Paul SM: Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur J Neurosci 2001, 14:474-482.
• [72]Yamada M, Chiba T, Sasabe J, Nawa M, Tajima H, Niikura T, Terashita K, Aiso S, Kita Y, Matsuoka M, Nishimoto I: Implanted cannula-mediated repetitive administration of Abeta25-35 into the mouse cerebral ventricle effectively impairs spatial working memory. Behav Brain Res 2005, 164:139-146.
• [73]McGeer PL, Itagaki S, Tago H, McGeer EG: Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 1987, 79:195-200.
• [74]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. BioMed Central Full Text
• [75]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 2004, 279:49523-49532.
• [76]Wajant H, Pfizenmaier K, Scheurich P: Tumor necrosis factor signaling. Cell Death Differ 2003, 10:45-65.
• [77]Grell M, Wajant H, Zimmermann G, Scheurich P: The type 1 receptor (CD120a) is the high-affinity receptor for soluble tumor necrosis factor. Proc Natl Acad Sci USA 1998, 95:570-575.
• [78]Fontaine V, Mohand-Said S, Hanoteau N, Fuchs C, Pfizenmaier K, Eisel U: Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. J Neurosci 2002, 22:RC216.
• [79]Yang L, Lindholm K, Konishi Y, Li R, Shen Y: Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways. J Neurosci 2002, 22:3025-3032.
• [80]Marchetti L, Klein M, Schlett K, Pfizenmaier K, Eisel UL: Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway. J Biol Chem 2004, 279:32869-32881.
• [81]Grell M, Douni E, Wajant H, Löhden M, Clauss M, Maxeiner B, Georgopoulos S, Lesslauer W, Kollias G, Pfizenmaier K, Scheurich P: The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 1995, 83:793-802.
• [82]Grell M: Tumor necrosis factor (TNF) receptors in cellular signaling of soluble and membrane-expressed TNF. J Inflammation 1995–1996, 47:8-17.
• [83]Stellwagen D, Malenka RC: Synaptic scaling mediated by glial TNF-alpha. Nature 2006, 440(7087):1054-1059.
• [84]Montgomery SL, Mastrangelo MA, Habib D, Narrow WC, Knowlden SA, Wright TW, Bowers WJ: Ablation of TNF-RI/RII expression in Alzheimer’s disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-α suppressive therapeutic strategies in the brain. Am J Pathol 2011, 179:2053-2070.
• [85]Golan H, Levav T, Mendelsohn A, Huleihel M: Involvement of tumor necrosis factor alpha in hippocampal development and function. Cereb Cortex 2004, 14:97-105.
• [86]Bernardino L, Agasse F, Silva B, Ferreira R, Grade S, Malva JO: Tumor necrosis factor-alpha modulates survival, proliferation, and neuronal differentiation in neonatal subventricular zone cell cultures. Stem Cells 2008, 26:2361-2371.
• [87]Iosif RE, Ekdahl CT, Ahlenius H, Pronk CJ, Bonde S, Kokaia Z, Jacobsen SE, Lindvall O: Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. J Neurosci 2006, 26:9703-9712.
• [88]Fioravanzo L, Venturini M, Liddo RD, Marchi F, Grandi C, Parnigotto PP, Folin M: Involvement of rat hippocampal astrocytes in β-amyloid-induced angiogenesis and neuroinflammation. Curr Alzheimer Res 2010, 7:591-601.
• [89]Belarbi K, Arellano C, Ferguson R, Jopson T, Rosi S: Chronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Brain Behav Immun 2012, 26:18-23.
• [90]Eleutherakis-Papaiakovou V, Bamias A, Dimopoulos MA: Thalidomide in cancer medicine. Ann Oncol 2004, 15:1151-1160.