Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of human β-amyloid

Journal of Neuroinflammation

Linda J Van Eldik³  Emmet Hirsch¹  D Martin Watterson²  Jeffrey M Craft³ 

[1] Department of Obstetrics and Gynecology, Evanston Northwestern Healthcare, Evanston, IL, USA;Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

关键词: microglia;    interleukin-1;    glial activation;    animal model;    amyloid beta;    Alzheimer's disease;   

Others  :  1213668
DOI  :  10.1186/1742-2094-2-15

 received in 2005-05-24, accepted in 2005-06-20,  发布年份 2005

【 摘 要 】

Background

Interleukin 1 (IL-1) is a key mediator of immune responses in health and disease. Although classically the function of IL-1 has been studied in the systemic immune system, research in the past decade has revealed analogous roles in the CNS where the cytokine can contribute to the neuroinflammation and neuropathology seen in a number of neurodegenerative diseases. In Alzheimer's disease (AD), for example, pre-clinical and clinical studies have implicated IL-1 in the progression of a pathologic, glia-mediated pro-inflammatory state in the CNS. The glia-driven neuroinflammation can lead to neuronal damage, which, in turn, stimulates further glia activation, potentially propagating a detrimental cycle that contributes to progression of pathology. A prediction of this neuroinflammation hypothesis is that increased IL-1 signaling in vivo would correlate with increased severity of AD-relevant neuroinflammation and neuronal damage.

Methods

To test the hypothesis that increased IL-1 signaling predisposes animals to beta-amyloid (Aβ)-induced damage, we used IL-1 receptor antagonist Knock-Out (IL1raKO) and wild-type (WT) littermate mice in a model that involves intracerebroventricular infusion of human oligomeric Aβ1–42. This model mimics many features of AD, including robust neuroinflammation, Aβ plaques, synaptic damage and neuronal loss in the hippocampus. IL1raKO and WT mice were infused with Aβ for 28 days, sacrificed at 42 days, and hippocampal endpoints analyzed.

Results

IL1raKO mice showed increased vulnerability to Aβ-induced neuropathology relative to their WT counterparts. Specifically, IL1raKO mice exhibited increased mortality, enhanced microglial activation and neuroinflammation, and more pronounced loss of synaptic markers. Interestingly, Aβ-induced astrocyte responses were not significantly different between WT and IL1raKO mice, suggesting that enhanced IL-1 signaling predominately affects microglia.

Conclusion

Our data are consistent with the neuroinflammation hypothesis whereby increased IL-1 signaling in AD enhances glia activation and leads to an augmented neuroinflammatory process that increases the severity of neuropathologic sequelae.

【 授权许可】

   
2005 Craft et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Allan SM, Rothwell NJ: Inflammation in central nervous system injury. Philos Trans R Soc Lond B Biol Sci 2003, 358:1669-1677.
• [2]Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T: Inflammation and Alzheimer's disease. Neurobiol Aging 2000, 21:383-421.
• [3]Griffin WST, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE: Glial-Neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression. Brain Pathol 1998, 8:65-72.
• [4]Craft JM, Watterson DM, Frautschy SA, Van Eldik LJ: Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivo. Neurobiol Aging 2004, 25:1283-1292.
• [5]Craft JM, Van Eldik LJ, Zasadzki M, Hu W, Watterson DM: Aminopyridazines attenuate hippocampus-dependent behavioral deficits induced by human beta-amyloid in a murine model of neuroinflammation. J Mol Neurosci 2004, 24:115-122.
• [6]Hu W, Ranaivo HR, Craft JM, Van Eldik LJ, Watterson DM: Validation of the neuroinflammation cycle as a drug discovery target using integrative chemical biology and lead compound development with an Alzheimer's disease-related mouse model. Cur Alzheim Res 2005, 2:197-205.
• [7]Mirzoeva S, Sawkar A, Zasakzki M, Guo L, Velentza AV, Dunlap V, Bourguignon JJ, Ramstrom H, Haiech J, Van Eldik LJ, Watterson DM: Discovery of a 3-amino-6-phenyl-pyridazine derivative as a new synthetic antineuroinflammatory compound. J Med Chem 2002, 45:563-566.
• [8]Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, Cole GM: Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci 2000, 20:5709-5714.
• [9]Griffin WS, Sheng JG, Roberts GW, Mrak RE: Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution. J Neuropathol Exp Neurol 1995, 54:276-281.
• [10]Sheng JG, Mrak RE, Griffin WS: Glial-neuronal interactions in Alzheimer disease: progressive association of IL-1alpha+ microglia and S100beta+ astrocytes with neurofibrillary tangle stages. J Neuropathol Exp Neurol 1997, 56:285-290.
• [11]Sheng JG, Mrak RE, Griffin WS: Microglial interleukin-1 alpha expression in brain regions in Alzheimer's disease: correlation with neuritic plaque distribution. Neuropathol Appli Neurobiol 1995, 21:290-301.
• [12]Das S, Potter H: Expression of the Alzheimer amyloid-promoting factors α1-antichymotrypsin and apolipoprotein E is induced in astrocytes by IL-1. Neuron 1995, 14:447-456.
• [13]Woiciechowsky C, Schoning B, Stoltenburg-Didinger G, Stockhammer F, Volk HD: Brain-IL-1 beta triggers astrogliosis through induction of IL-6: inhibition by propranolol and IL-10. Med Sci Monit 2004, 10:BR325-330.
• [14]Sheng JG, Ito K, Skinner RD, Mrak RE, Rovnaghi CR, Van Eldik LJ, Griffin WS: In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis. Neurobiol Aging 1996, 17:761-766.
• [15]Akama KT, Van Eldik LJ: Beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1beta- and tumor necrosis factor-alpha (TNFalpha)-dependent, and involves a TNFalpha receptor-associated factor- and NFkappaB-inducing kinase-dependent signaling mechanism. J Biol Chem 2000, 275:7918-7924.
• [16]Mrak RE, Griffin WS: Interleukin-1, neuroinflammation, and Alzheimer's disease. Neurobiol Aging 2001, 22:903-908.
• [17]Nicoll JA, Mrak RE, Graham DI, Stewart J, Wilcock G, MacGowan S, Esiri MM, Murray LS, Dewar D, Love S, Moss T, Griffin WS: Association of interleukin-1 gene polymorphisms with Alzheimer's disease. Ann Neurol 2000, 47:365-368.
• [18]Hirsch E, Irikura VM, Paul SM, Hirsh D: Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc Natl Acad Sci U S A 1996, 93:11008-11013.
• [19]Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ: Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 2002, 277:32046-32053.
• [20]Frautschy SA, Yang F, Calderon L, Cole GM: Rodent models of Alzheimer's disease: rat Aβ infusion approaches to amyloid deposits. Neurobiol Aging 1996, 17:311-321.
• [21]Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM: Phenolic anti-inflammatory antioxidant reversal of Aβ-induced cognitive deficits and neuropathology. Neurobiol Aging 2001, 22:993-1005.
• [22]Hayakata T, Shiozaki T, Tasaki O, Ikegawa H, Inoue Y, Toshiyuki F, Hosotubo H, Kieko F, Yamashita T, Tanaka H, Shimazu T, Sugimoto H: Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury. Shock 2004, 22:102-107.
• [23]Hu X, Nesic-Taylor O, Qiu J, Rea HC, Fabian R, Rassin DK, Perez-Polo JR: Activation of nuclear factor-kappaB signaling pathway by interleukin-1 after hypoxia/ischemia in neonatal rat hippocampus and cortex. J Neurochem 2005, 93:26-37.
• [24]Basu A, Lazovic J, Krady JK, Mauger DT, Rothstein RP, Smith MB, Levison SW: Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury. J Cereb Blood Flow Metab 2005, 25:17-29.
• [25]Sarchielli P, Galli F, Floridi A, Floridi A, Gallai V: Relevance of protein nitration in brain injury: a key pathophysiological mechanism in neurodegenerative, autoimmune, or inflammatory CNS diseases and stroke. Amino Acids 2003, 25:427-36.
• [26]Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL 3rd, Araoz C: Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 1989, 86:7611-7615.
• [27]Van Everbroeck B, Dewulf E, Pals P, Lubke U, Martin JJ, Cras P: The role of cytokines, astrocytes, microglia and apoptosis in Creutzfeldt-Jakob disease. Neurobiol Aging 2002, 23:59-64.
• [28]Mrak RE, Griffin WS: The role of chronic self-propagating glial responses in neurodegeneration: implications for long-lived survivors of human immunodeficiency virus. J Neurovirol 1997, 3:241-246.
• [29]Craft JM, Watterson DM, Marks A, Van Eldik LJ: Enhanced susceptibility of S-100B transgenic mice to neuroinflammation and neuronal dysfunction induced by intracerebroventricular infusion of human beta-amyloid. Glia 2005. available online Apr 4
• [30]Griffin WS, Sheng JG, Gentleman SM, Graham DI, Mrak RE, Roberts GW: Microglial interleukin-1 alpha expression in human head injury: correlations with neuronal and neuritic beta-amyloid precursor protein expression. Neurosci Lett 1994, 176:133-136.
• [31]Mortimer JA, van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A, Jorm AF, Kokmen E, Kondo K, Rocca WA, EURODEM Risk Factors Research Group: Head trauma as a risk factor for Alzheimer's disease: a collaborative re-analysis of case-control studies. Int J Epidemiol 1991, 20(Suppl 2):S28-35.
• [32]Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C: Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003, 61:46-54.