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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2008

Open Access 01-12-2008 | Research

Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation

Authors: Jae Woong Lee, Yong Kyung Lee, Dong Yeon Yuk, Dong Young Choi, Sang Bae Ban, Ki Wan Oh, Jin Tae Hong

Published in: Journal of Neuroinflammation | Issue 1/2008

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Abstract

Background

Alzheimer's disease (AD) is characterized by extensive loss of neurons in the brain of AD patients. Intracellular accumulation of beta-amyloid peptide (Aβ) has also shown to occur in AD. Neuro-inflammation has been known to play a role in the pathogenesis of AD.

Methods

In this study, we investigated neuro-inflammation and amyloidogenesis and memory impairment following the systemic inflammation generated by lipopolysaccharide (LPS) using immunohistochemistry, ELISA, behavioral tests and Western blotting.

Results

Intraperitoneal injection of LPS, (250 μg/kg) induced memory impairment determined by passive avoidance and water maze tests in mice. Repeated injection of LPS (250 μg/kg, 3 or 7 times) resulted in an accumulation of Aβ1–42 in the hippocampus and cerebralcortex of mice brains through increased β- and γ-secretase activities accompanied with the increased expression of amyloid precursor protein (APP), 99-residue carboxy-terminal fragment of APP (C99) and generation of Aβ1–42 as well as activation of astrocytes in vivo. 3 weeks of pretreatment of sulindac sulfide (3.75 and 7.5 mg/kg, orally), an anti-inflammatory agent, suppressed the LPS-induced amyloidogenesis, memory dysfunction as well as neuronal cell death in vivo. Sulindac sulfide (12.5–50 μM) also suppressed LPS (1 μg/ml)-induced amyloidogenesis in cultured neurons and astrocytes in vitro.

Conclusion

This study suggests that neuro-inflammatory reaction could contribute to AD pathology, and anti-inflammatory agent could be useful for the prevention of AD.
Appendix
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Literature
1.
Mattson MP, Maudsley S, Martin B: A neural signaling triumvirate that influences ageing and age-related disease: insulin/IGF-1, BDNF and serotonin. Ageing Res Rev. 2004, 3: 445-464. 10.1016/j.arr.2004.08.001.CrossRefPubMed
2.
Pratico D, Trojanowski JQ: Inflammatory hypotheses: novel mechanisms of Alzheimer's neurodegeneration and new therapeutic targets?. Neurobiol Aging. 2000, 21: 441-445. 10.1016/S0197-4580(00)00141-X.CrossRefPubMed
3.
Masliah E, LiCastro F: Neurodegenerative dementias: clinical features and pathological mechanisms. 2000, New York, McGraw-Hill
4.
Neuroinflammation Working Group: Inflammation and Alzheimer's disease. Neurobiol Aging. 2000, 21: 383-421. 10.1016/S0197-4580(00)00124-X.PubMedCentralCrossRef
5.
Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJ, Rozemuller JM, Veerhuis R, Williams A: Neuroinflammation in Alzheimer's disease and prion disease. Glia. 2002, 40: 232-239. 10.1002/glia.10146.CrossRefPubMed
6.
McGeer EG, McGeer PL: Inflammatory processes in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatr. 2003, 27: 741-749. 10.1016/S0278-5846(03)00124-6.CrossRef
7.
Guo JT, Yu J, Grass D, de Beer FC, Kindy MS: Inflammation-dependent cerebral deposition of serum amyloid a protein in a mouse model of amyloidosis. J Neurosci. 2002, 22: 5900-5909.PubMed
8.
Hirose Y, Imai Y, Nakajima K, Takemoto N, Toya S, Kohsaka S: Glial conditioned medium alters the expression of amyloid precursor protein in SH-SY5Y neuroblastoma cells. Biochem Biophys Res Commun. 1994, 198: 504-509. 10.1006/bbrc.1994.1074.CrossRefPubMed
9.
Buxbaum JD, Oishi M, Chen HI, Pinkas-Kramarski R, Jaffe EA, Gandy SE, Greengard P: Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. Proc Natl Acad Sci USA. 1992, 89: 10075-10078. 10.1073/pnas.89.21.10075.PubMedCentralCrossRefPubMed
10.
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: 63-68.PubMed
11.
Sastre M, Dewatcher I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Heneka MT: Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci. 2003, 23: 9796-9804.PubMed
12.
Vassar R: The beta-secretase, BACE: a prime drug target for Alzheimer's disease. J Mol Neurosci. 2001, 17: 157-70. 10.1385/JMN:17:2:157.CrossRefPubMed
13.
Walter J, Kaether C, Steiner H, Haass C: The cell biology of Alzheimer's disease: uncovering the secrets of secretases. Curr Opin Neurobiol. 2001, 11: 585-590. 10.1016/S0959-4388(00)00253-1.CrossRefPubMed
14.
McGeer PL, Rogers J: Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease. Neurology. 1992, 42: 447-449.CrossRefPubMed
15.
Eikelenboom P, Zhan SS, Van Gool WA, Allsop D: Inflammatory mechanisms in Alzheimer's disease. Trends Pharmacol Sci. 1994, 15: 447-450. 10.1016/0165-6147(94)90057-4.CrossRefPubMed
16.
Perry VH: The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun. 2004, 18: 407-413. 10.1016/j.bbi.2004.01.004.CrossRefPubMed
17.
Sparkman NL, Martin LA, Calvert WS, Boehm GW: Effects of intraperitoneal lipopolysaccharide on Morris maze performance in year-old and 2-month-old female C57BL/6J mice. Behav Brain Res. 2005, 159: 145-151. 10.1016/j.bbr.2004.10.011.CrossRefPubMed
18.
Shaw KN, Commins S, O'Mara SM: Lipopolysaccharide causes deficits in spatial learning in the water maze but notin BDNF expression in the rat dentate gyrus. Behav Brain Res. 2001, 124: 47-54. 10.1016/S0166-4328(01)00232-7.CrossRefPubMed
19.
Vernet-der Garabedian B, Lemaigre-Dubreuil Y, Delhaye-Bouchaud N, Mariani J: Abnormal IL-1beta cytokine expression in the cerebellum of the ataxic mutant mice staggerer and lurcher. Brain Res Mol Brain Res. 1998, 62: 224-227. 10.1016/S0169-328X(98)00268-X.CrossRefPubMed
20.
Morris R: Developments of water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984, 11: 47-60. 10.1016/0165-0270(84)90007-4.CrossRefPubMed
21.
Park KS, Lee RD, Kang SK, Han SY, Park KL, Yang KH, Song YS, Park HJ, Lee YM, Yun YP, Oh KW, Kim DJ, Yun YW, Hwang SJ, Lee SE, Hong JT: Neuronal differentiation of embryonic midbrain cells by upregulation ofperoxisome proliferator-activated receptor-gamma via the JNK-dependent pathway. Exp Cell Res. 2004, 297: 424-433. 10.1016/j.yexcr.2004.03.034.CrossRefPubMed
22.
Lee SM, Nguyen TH, Park MH, Kim KS, Cho KJ, Moon DC, Kim HY, Yoon DY, Hong JT: EPO receptor-mediated ERK kinase and NF-kappaB activation in erythropoietin-promoted differentiation of astrocytes. Biochem Biophys Res Commun. 2004, 320: 1087-1095. 10.1016/j.bbrc.2004.06.060.CrossRefPubMed
23.
Culpan D, Cram D, Chalmers K, Cornish A, Palmer L, Palmer J, Hughes A, Passmore P, Craigs D, Wilcock GK, Kehoe PG, Love S: TNFR-associated factor-2 (TRAF-2) in Alzheimer's disease. Neurobiol Aging. 2007 Dec 5.
24.
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 beta generation and prevents learning and memory deficits in Alzheimer's mice. J Cell Biol. 2007, 178: 829-41. 10.1083/jcb.200705042.PubMedCentralCrossRefPubMed
25.
Gasparini L, Rusconi L, Xu H, del Soldato P, Ongini E: Modulation of beta-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures. J Neurochem. 2004, 88: 337-348.CrossRefPubMed
26.
Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G: Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci. 2003, 23: 7504-7509.PubMed
27.
Blasko I, Apochal A, Boeck G, Hartmann T, Grubeck-Loebenstein B, Ransmayr G: Ibuprofen decreases cytokine-induced amyloid beta production in neuronal cells. Neurobiol Dis. 2001, 8: 1094-1101. 10.1006/nbdi.2001.0451.CrossRefPubMed
28.
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.PubMed
29.
Sung S, Yang H, Uryu K, Lee EB, Zhao L, Shineman D, Trojanowski JQ, Lee VM, Pratico D: Modulation of nuclear factor-kappa B activity by indomethacin influences A beta levels but not A beta precursor protein metabolism in a model of Alzheimer's disease. Am J Pathol. 2004, 165: 2197-2206.PubMedCentralCrossRefPubMed
30.
Hwang DY, Cho JS, Lee SH, Chae KR, Lim HJ, Min SH, Seo SJ, Song YS, Song CW, Paik SG, Sheen YY, Kim YK: Aberrant expressions of pathogenic phenotype in Alzheimer's diseased transgenic mice carrying NSE-controlled APPsw. Exp Neurol. 2004, 186: 20-32. 10.1016/j.expneurol.2003.09.021.CrossRefPubMed
31.
Kuperstein F, Brand A, Yavin E: Amyloid Abeta1-40 preconditions non-apoptotic signals in vivo and protects fetal rat brain from intrauterine ischemic stress. J Neurochem. 2004, 91: 965-974. 10.1111/j.1471-4159.2004.02778.x.CrossRefPubMed
32.
Zou K, Kim D, Kakio A, Byun K, Gong JS, Kim J, Kim M, Sawamura N, Nishimoto S, Matsuzaki K, Lee B, Yanagisawa K, Michikawa M: Amyloid beta-protein (Abeta)1-40 protects neurons from damage induced by Abeta1-42 in culture and in rat brain. J Neurochem. 2003, 87: 609-619. 10.1046/j.1471-4159.2003.02018.x.CrossRefPubMed
33.
Zou K, Gong JS, Yanagisawa K, Michikawa M: A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci. 2002, 22: 4833-4841.PubMed
34.
Hauss-Wegrzyniak B, Wenk GL: Beta-amyloid deposition in the brains of rats chronically infused with thiorphan or lipopolysaccharide: the role of ascorbic acid in the vehicle. Neurosci Lett. 2002, 322: 75-78. 10.1016/S0304-3940(02)00087-3.CrossRefPubMed
35.
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. 10.1074/jbc.M402034200.CrossRefPubMed
36.
Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE: Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulationof amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis. 2003, 14: 133-145. 10.1016/S0969-9961(03)00069-X.CrossRefPubMed
37.
Rogers JT, Leiter LM, McPhee J, Cahill CM, Zhan SS, Potter H, Nilsson LN: Translation of the Alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5'-untranslated region sequences. J Biol Chem. 1999, 274: 6421-6431. 10.1074/jbc.274.10.6421.CrossRefPubMed
38.
Bandyopadhyay S, Hartley DM, Cahill CM, Lahiri DK, Chattopadhyay N, Rogers JT: Interleukin-1alpha stimulates non-amyloidogenic pathway by alpha-secretase(ADAM-10 and ADAM-17) cleavage of APP in human astrocytic cells involving p38 MAP kinase. J Neurosci Res. 2006, 84: 106-118. 10.1002/jnr.20864.CrossRefPubMed
39.
Ma G, Chen S, Wang X, Ba M, Yang H, Lu G: Short-term interleukin-1(beta) increases the release of secreted APP(alpha) via MEK1/2-dependent and JNK-dependent alpha-secretase cleavage in neuroglioma U251 cells. J Neurosci Res. 2005, 80: 683-692. 10.1002/jnr.20515.CrossRefPubMed
40.
Salbaum JM, Weidemann A, Lemaire HG, Masters CL, Beyreuther K: The promoter of Alzheimer's disease amyloid A4 precursor gene. EMBO J. 1988, 7: 2807-2813.PubMedCentralPubMed
41.
Quitschke WW, Goldgaber D: The amyloid beta-protein precursor promoter. A region essential for transcriptional activity contains a nuclear factor binding domain. J Biol Chem. 1992, 267: 17362-17368.PubMed
42.
Williams T, Tjian R: Analysis of the DNA-binding and activation properties of the human transcription factor AP-2. Genes Dev. 1991, 5: 670-682. 10.1101/gad.5.4.670.CrossRefPubMed
43.
Trejo J, Massamiri T, Deng T, Dewji NN, Bayney RM, Brown JH: A direct role for protein kinase C and the transcription factor Jun/AP-1 in the regulation of the Alzheimer's beta-amyloid precursor protein gene. J Biol Chem. 1994, 269: 21682-21690.PubMed
44.
Hashimoto Y, Chiba T, Yamada M, Nawa M, Kanekura K, Suzuki H, Terashita K, Aiso S, Nishimoto I, Matsuoka M: Transforming growth factor beta2 is a neuronal death-inducing ligand for amyloid-beta precursor protein. Mol Cell Biol. 2005, 25: 9304-9317. 10.1128/MCB.25.21.9304-9317.2005.PubMedCentralCrossRefPubMed
45.
Hensley K, Floyd RA, Zheng NY, Nael R, Robinson KA, Nguyen X, Pye QN, Stewart CA, Geddes J, Markesbery WR, Patel E, Johnson GV, Bing G: p38 kinase is activated in the Alzheimer's disease brain. J Neurochem. 1999, 72: 2053-2058. 10.1046/j.1471-4159.1999.0722053.x.CrossRefPubMed
46.
Giovannini MG, Scali C, Prosperi C, Bellucci A, Vannucchi MG, Rosi S, Pepeu G, Casamenti F: Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway. Neurobiol Dis. 2002, 11: 257-274. 10.1006/nbdi.2002.0538.CrossRefPubMed
47.
Noble F, Rubira E, Boulanouar M, Palmier B, Plotkine M, Warnet JM, Marchand-Leroux C, Massicot F: Acute systemic inflammation induces central mitochondrial damage and mnesic deficit in adult Swiss mice. Neurosci Lett. 2007, 424: 106-110. 10.1016/j.neulet.2007.07.005.CrossRefPubMed
48.
Milatovic D, Zaja-Milatovic S, Montine KS, Horner PJ, Montine TJ: Pharmacologic suppression of neuronal oxidative damage and dendritic degeneration following direct activation of glial innate immunity in mouse cerebrum. J Neurochem. 2003, 87: 1518-1526.CrossRefPubMed
49.
Szczepanik AM, Ringheim GE: IL-10 and glucocorticoids inhibit Abeta(1-42)- and lipopolysaccharide-induced pro-inflammatory cytokine and chemokine induction in the central nervous system. J Alzheimers Dis. 2003, 5: 105-117.PubMed
50.
Jang JH, Surh YJ: Beta-amyloid-induced apoptosis is associated with cyclooxygenase-2 up-regulation via the mitogen-activated protein kinase-NF-kappaB signaling pathway. Free Radic Biol Med. 2005, 38: 1604-1613. 10.1016/j.freeradbiomed.2005.02.023.CrossRefPubMed
51.
Song YS, Park HJ, Kim SY, Lee SH, Yoo HS, Lee HS, Lee MK, Oh KW, Kang SK, Lee SE, Hong JT: Protective role of Bcl-2 on beta-amyloid-induced cell death of differentiated PC12 cells: reduction of NF-kappaB and p38 MAP kinase activation. Neurosci Res. 2004, 49: 69-80. 10.1016/j.neures.2004.01.010.CrossRefPubMed
52.
Bate C, Kempster S, Last V, Williams A: Interferon-gamma increases neuronal death in response to amyloid-beta1-42. J Neuroinflammation. 2006, 3: 7-10.1186/1742-2094-3-7.PubMedCentralCrossRefPubMed
53.
Hashimoto Y, Nawa M, Chiba T, Aiso S, Nishimoto I, Matsuoka M: Transforming growth factor beta2 autocrinally mediates neuronal cell death induced by amyloid-beta. J Neurosci Res. 2006, 83: 1039-1047. 10.1002/jnr.20804.CrossRefPubMed
54.
Culbert AA, Skaper SD, Howlett DR, Evans NA, Facci L, Soden PE, Seymour ZM, Guillot F, Gaestel M, Richardson JC: MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity. Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease. J Biol Chem. 2006, 281: 23658-23667. 10.1074/jbc.M513646200.CrossRefPubMed
Metadata
Title
Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation
Authors
Jae Woong Lee
Yong Kyung Lee
Dong Yeon Yuk
Dong Young Choi
Sang Bae Ban
Ki Wan Oh
Jin Tae Hong
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2008
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-5-37

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